A novel GPR143 duplication mutation in a Chinese family with X-linked congenital nystagmus
PMID: 19390656
Gene: GPR143
HGNC: 20145
Disease: X-linked recessive ocular albinism
MONDO: 0021019
InheritancePattern: X-linked recessive
Prevalence: Ocular albinism has an estimated prevalence between 1 in 111,000 and 1 in 1,000,000 live births (PMID: 35495622)
Penetrance: Fully penetrant in males, with onset in infancy. Most female carriers appear to be unaffected.
In this study, we present a four-generation Chinese family with X-linked CN. All affected individuals exhibited nystagmus but without any typical signs of OA1. Upon genetic analysis, we characterized the underlying molecular defect as a novel 19 base pair (bp) duplication in exon 1 of GPR143, causing a frame-shift in all affected males.
Case#: Peng_2009_Patient_IV:3, male, age of onset not reported, family origin reported to be from China
CasePresentingHPOs: HP:0006934 (Congenital nystagmus)
CaseHPOFreeText: The proband has been diagnosed with congenital nystagmus, with family members showing an X-linked pattern of inheritance.
CaseNotHPOs: N/A
CaseNotHPOFreeText: The affected individuals are described as lacking the typical signs of ocular albinism 1, but details have not been described.
CasePreviousTesting: Genotyping was initially performed by linkage mapping using markers on the X chromosome.
CaseMethod1: linkage analysis
CaseMethod2: Sanger sequencing
CaseGenotypingMethod: Genotyping was initially performed by linkage mapping using markers on the X chromosome, followed by Sanger sequencing of PCR products from each exon of the GPR143 gene. Family members were subsequently genotyped by allele-specific PCR.
Variant: The proband harbors the NM_000273.3:c.291_309dup (p.Asp104PhefsTer3) variant in the hemizygous state.
CAID: CA2573320693
gnomAD: This variant was not found in gnomAD v2.1.1.
VariantEvidence: NM_000273.3:c.291_309dup (p.Asp104PhefsTer3) is a frameshift variant in exon 2 of 9, and is predicted to trigger nonsense-mediated decay or to at least truncate the C-terminal 75% of the protein product.
CaseAddInfo: The proband is from a family with at least three other affected males who also harbor the variant.
CasePMIDs: N/A
To study the function of GPR143, we investigated the phenotypic effect of overexpression of GPR143 in pheochromocytoma (PC12) cells treated with nerve growth factor. Overexpression of mouse GPR143 inhibited neurite outgrowth, and the effect was mitigated by l-DOPA cyclohexylester, an antagonist for l-DOPA. Furthermore, knockdown of G-protein Gα13 attenuated mouse GPR143 induced inhibition of neurite outgrowth. Human wild-type (wt) GPR143 also inhibited neurite outgrowth, but its mutants did not mimic the effect of wt GPR143. Our results provide a mechanism for axon guidance phenotype in ocular albinism 1.
ExperimentName: GPR143 over-expression in neuroendocrine tumor cells
NonPatientCell: CL:0000336 (adrenal medulla chromaffin cell, specifically the PC-12 cell line)
GeneFunction: GO:0031175 (neuron projection development)
GeneAlteration: Over-expression of GPR143 was accomplished by stable transfection of PC-12 cells with mCherry-tagged wild-type or mutant GPR143.
FunctionalEvidence: Figure 4C indicates that GPR143 over-expression decreases the # of neurites longer than 100 microns, and that this occurs through a mechanism that is dependent on the G-protein Galpha13. Figure 5E shows that this effect of wild-type GPR143 is particularly pronounced for neurites longer than 150 microns, and is not mimicked by GPR143 missense variants reported in patients.
FAVariants: Patient-associated variants were p.Asp78Asn (ClinVar: 98620), p.Trp133Arg (ClinVar: 10516 or 10519), p.Ile261Asn (CAID: CA411996177), and p.Trp292Gly (ClinVar: 98647).
Overexpression of the gene product of ocular albinism 1 (GPR143/OA1) but not its mutant forms inhibits neurite outgrowth in PC12 cells
PMID: 31606330
Gene: GPR143
HGNC: 20145
Disease: X-linked recessive ocular albinism
MONDO: 0021019
InheritancePattern: X-linked recessive
Prevalence: Ocular albinism has an estimated prevalence between 1 in 111,000 and 1 in 1,000,000 live births (PMID: 35495622)
Penetrance: Fully penetrant in males, with onset in infancy. Most female carriers appear to be unaffected.
All nine exons of the OA1 gene, as well as the 5' and 3' untranslated regions, were scanned for point mutations in PCR-amplified DNA from 60 OA1 patients. The mutations identified include: two frameshifts
Case#: Schiaffino_1995_Family_2948_Patient_BA442, male, age not reported, family origin reported as British in two previous publications
CasePresentingHPOs: N/A
CaseHPOFreeText: The proband has been diagnosed with ocular albinism 1.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: The patient's family was included in two previous linkage mapping studies (PMID: 1355560, PMID: 8301646).
CaseMethod1: Linkage mapping
CaseMethod2: Sanger sequencing
CaseGenotypingMethod: The patient's family was included in two previous linkage mapping studies (PMID: 1355560, PMID: 8301646), and the proband was genotyped in this study by Sanger sequencing of PCR products from the 9 exons of GPR143.
Variant: The proband harbors the NM_000273.3(GPR143):c.216_232del (p.Ala73fs) variant in the hemizygous state.
ClinVar: 98619
gnomAD: This variant was not found in gnomAD v2.1.1.
VariantEvidence: NM_000273.3(GPR143):c.216_232del (p.Ala73fs) is a frameshift variant in exon 1 of 9, and is predicted to trigger nonsense-mediated decay or to at least truncate the C-terminal 82% of the protein product.
CaseAddInfo: The variant observed in this proband has been previously reported in two other studies (PMID: 1355560, PMID: 8301646).
CasePMIDs: PMID: 1355560, PMID: 8301646
Analysis of the OA1 gene reveals mutations in only one-third of patients with X-linked ocular albinism
PMID: 8634705
Gene: GPR143
HGNC: 20145
Disease: X-linked recessive ocular albinism
MONDO: 0021019
InheritancePattern: X-linked recessive
Prevalence: Ocular albinism has an estimated prevalence between 1 in 111,000 and 1 in 1,000,000 live births (PMID: 35495622)
Penetrance: Fully penetrant in males, with onset in infancy. Most female carriers appear to be unaffected.
We studied a large Chinese family with nystagmus as a prominent and consistent manifestation phenotype in nine patients to map and identify a disease-causing gene for nystagmus. X-linked recessive inheritance was observed in the family, and foveal hypoplasia was detected in some of the nine patients. The disease gene was mapped to an approximately 10.6 Mb region flanked by DXS996 and DXS7593 on Xp22 with a significant peak multipoint LOD score. Analysis of 21 candidate genes in the region revealed a novel p.S89F mutation in the second transmembrane domain of GPR143, a G protein-coupled receptor which causes ocular albinism when mutated. All male patients in the family were hemizygous for the mutation; the female carriers were heterozygous for the mutation.
FamilyLabel: Liu_2007_Family
Family#PresentingHPOs: HP:0006934 (Congenital nystagmus), HP:0007750 (Hypoplasia of the fovea), HP:0000483 (Astigmatism), HP:0007663 (Reduced visual acuity)
FamilyPresentingHPOFreeText: The affected family members have been diagnosed with congenital nystagmus segregating with an X-linked mode of inheritance. While all members exhibit nystagmus, some members have foveal hypoplasia (4 out of 5 affected males), myopia, amblyopia, and/or mottling of the retinal pigmentation as well.
FamilyNotHPOs: HP:0001000 (Abnormality of skin pigmentation), HP:0009887 (Abnormality of hair pigmentation), HP:0012805 (Iris transillumination defect), HP:0007894 (Hypopigmentation of the fundus)
FamilyNotHPOFreeText: One family member was subjected to functional MRI and did not show abnormalities of the optic nerve head.
CountryOrigin: China
Ethnicity: Chinese
Race: Not specifically described
Family#PreviousTesting: Linkage mapping has been performed in affected and unaffected family members using 33 polymorphic markers along the entire X chromosome. Haplotype analysis identified a shared region of approximately 10.6 Mb in all affected males.
Family#Method1: Linkage mapping and haplotype analysis
Family#Method2: Sanger sequencing of 21 candidate genes in the linkage region
Family#GenotypingMethod: Linkage mapping has been performed in affected and unaffected family members using 33 polymorphic markers along the entire X chromosome. Haplotype analysis identified a shared region of approximately 10.6 Mb in all affected males. Sanger sequencing was then performed for 21 candidate genes in the linkage region, followed by RFLP analysis in a subset of affected and unaffected family members.
Affected: 4 fully genotyped, 9 total
Unaffected: 7 fully genotyped
Segregations: 8 segregations are shown by the pedigree in Figure 2B.
PublishedLOD: 8.89 (associated with the DXS987 marker on chromosome Xp22)
eLOD: N/A
AddSegregationInfo: N/A
ProbandLabel: Liu_2007_Family_Patient_V-10
Variant: The affected male family members harbor the NM_000273.3(GPR143):c.266C>T (p.Ser89Phe) variant in the hemizygous state.
ClinVar: 10522
gnomAD: This variant was not found in gnomAD v2.1.1.
VariantEvidence: NM_000273.3(GPR143):c.266C>T (p.Ser89Phe) is a missense variant in exon 2 of 9 total, and is located in a transmembrane domain but does not have experimental evidence of gene impact.
FamilyAddInfo: The family is not reported to be consanguineous.
FamilyPMIDs: N/A
Identification of a novel GPR143 mutation in a large Chinese family with congenital nystagmus as the most prominent and consistent manifestation
PMID: 17516023
Gene: GPR143
HGNC: 20145
Disease: X-linked recessive ocular albinism
MONDO: 0021019
InheritancePattern: X-linked recessive
Prevalence: Ocular albinism has an estimated prevalence between 1 in 111,000 and 1 in 1,000,000 live births (PMID: 35495622)
Penetrance: Fully penetrant in males, with onset in infancy. Most female carriers appear to be unaffected.
p.S89F
Case#: Liu_2007_Family_Patient_V-10, male, age <6 months at time of onset, family origin reported to be Chinese
CasePresentingHPOs: HP:0006934 (Congenital nystagmus), HP:0000666 (Horizontal nystagmus), HP:0007750 (Hypoplasia of the fovea), HP:0000483 (Astigmatism), HP:0007663 (Reduced visual acuity), HP:0007814 (Retinal pigment epithelial mottling), HP:0000646 (Amblyopia)
CaseHPOFreeText: The proband and his affected family members have been diagnosed with congenital nystagmus segregating with an X-linked mode of inheritance.
CaseNotHPOs: HP:0001000 (Abnormality of skin pigmentation), HP:0009887 (Abnormality of hair pigmentation), HP:0012805 (Iris transillumination defect), HP:0007894 (Hypopigmentation of the fundus), HP:0000545 (Myopia)
CaseNotHPOFreeText: The patient did not exhibit abnormalities of the optic nerve head on functional MRI.
CasePreviousTesting: Linkage mapping has been performed in affected and unaffected family members using 33 polymorphic markers along the entire X chromosome. Haplotype analysis identified a shared region of approximately 10.6 Mb in all affected males.
CaseMethod1: Linkage mapping and haplotype analysis
CaseMethod2: Sanger sequencing of 21 candidate genes in the linkage region
CaseGenotypingMethod: Linkage mapping has been performed in the proband and affected and unaffected family members using 33 polymorphic markers along the entire X chromosome. Haplotype analysis identified a shared region of approximately 10.6 Mb in all affected males. Sanger sequencing was then performed for 21 candidate genes in the linkage region, followed by RFLP analysis in a subset of affected and unaffected family members.
Variant: The proband harbors the NM_000273.3(GPR143):c.266C>T (p.Ser89Phe) variant in the hemizygous state.
ClinVar: 10522
gnomAD: This variant was not found in gnomAD v2.1.1.
VariantEvidence: NM_000273.3(GPR143):c.266C>T (p.Ser89Phe) is a missense variant in exon 2 of 9 total, and is located in a transmembrane domain but does not have experimental evidence of gene impact.
CaseAddInfo: The proband is from a family with at least four other affected males and one affected female family member who also harbor the variant.
CasePMIDs: N/A
Cloning of the gene for ocular albinism type 1 from the distal short arm of the X chromosome
PMID: 7647783
Gene: GPR143
HGNC: 20145
Disease: X-linked recessive ocular albinism
MONDO: 0021019
InheritancePattern: X-linked recessive
Prevalence: Ocular albinism has an estimated prevalence between 1 in 111,000 and 1 in 1,000,000 live births (PMID: 35495622)
Penetrance: Fully penetrant in males, with onset in infancy. Most female carriers appear to be unaffected.
To address the function of OA1 in melanosome biogenesis, we have used siRNA inactivation and combined morphological and biochemical methods to investigate melanosome ultrastructure, melanosomal protein localization and expression in human pigmented melanocytic cells. OA1 loss of function leads to decreased pigmentation and causes formation of enlarged aberrant premelanosomes harboring disorganized fibrillar structures and displaying proteins of mature melanosomes and lysosomes at their membrane.
ExperimentName: GPR143 silencing in melanoma cells
NonPatientCell: CL:1000458 (melanocyte of skin, specifically the highly pigmented MNT-1 human melanoma cell line)
GeneFunction: GO:1903232 (melanosome assembly)
GeneAlteration: GPR143 silencing was accomplished by transient transfection of MNT-1 cells with specific siRNA, alongside a non-targeting siRNA control.
FunctionalEvidence: siRNA-treated cells exhibited 50% reduction in mature melanosomes and melanin-containing cells by immunofluorescence (Figures 2E, 2F, 2G). This was confirmed by electron microscopy (Figures 2H, 2I, 2J, 2K). GPR143 silencing also resulted in a combination of normal sized melanosomes and enlarged macromelanosome precursors (Figures 2I, S2A). These cellular defects are an approximate match to the giant melanosomes in the melanocytes of the human patients as well as the hypopigmentation of the fundus.
FAVariants: GPR143 disruption was siRNA-based, and patient-associated variants were not studied.
The ocular albinism type 1 (OA1) G-protein-coupled receptor functions with MART-1 at early stages of melanogenesis to control melanosome identity and composition
PMID: 19717472
Gene: GPR143
HGNC: 20145
Disease: X-linked recessive ocular albinism
MONDO: 0021019
InheritancePattern: X-linked recessive
Prevalence: Ocular albinism has an estimated prevalence between 1 in 111,000 and 1 in 1,000,000 live births (PMID: 35495622)
Penetrance: Fully penetrant in males, with onset in infancy. Most female carriers appear to be unaffected.
c.276G>A (p.W92X)
Case#: Zou_2017_Patient_F2-II:1, male, age 3 at time of report, family national origin reported to be from China
CasePresentingHPOs: HP:0000639 (Nystagmus), HP:0000613 (Photophobia), HP:0007663 (Reduced visual acuity), HP:0007750 (Hypoplasia of the fovea), HP:0007894 (Hypopigmentation of the fundus)
CaseHPOFreeText: The proband has been diagnosed with ocular albinism 1. Foveal hypoplasia was described as severe. Best-corrected visual acuity was limited to light perception.
CaseNotHPOs: HP:0007730 (Iris hypopigmentation)
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
CaseMethod1: Sanger sequencing
CaseMethod2: N/A
CaseGenotypingMethod: Patients were genotyped by Sanger sequencing of PCR products from the 9 exons of the GPR143 gene.
Variant: The proband harbors the NM_000273.3(GPR143):c.276G>A (p.Trp92Ter) variant in the hemizygous state.
CAID: CA411999243
gnomAD: This variant was not found in gnomAD v2.1.1.
VariantEvidence: NM_000273.3(GPR143):c.276G>A (p.Trp92Ter) is a nonsense variant in exon 2 of 9, and is predicted to trigger nonsense-mediated decay or to at least truncate the C-terminal 77% of the protein product.
CaseAddInfo: N/A
CasePMIDs: N/A
Molecular genetic and clinical evaluation of three Chinese families with X-linked ocular albinism
PMID: 28211458
Gene: GPR143
HGNC: 20145
Disease: X-linked recessive ocular albinism
MONDO: 0021019
InheritancePattern: X-linked recessive
Prevalence: Ocular albinism has an estimated prevalence between 1 in 111,000 and 1 in 1,000,000 live births (PMID: 35495622)
Penetrance: Fully penetrant in males, with onset in infancy. Most female carriers appear to be unaffected.
c.333_360+14del42insCTT
Case#: Zou_2017_Patient_F1-II:1, male, age 4 at time of report, family national origin reported to be from China
CasePresentingHPOs: HP:0000639 (Nystagmus), HP:0000613 (Photophobia), HP:0007663 (Reduced visual acuity), HP:0007750 (Hypoplasia of the fovea), HP:0007894 (Hypopigmentation of the fundus)
CaseHPOFreeText: The proband has been diagnosed with ocular albinism 1. Foveal hypoplasia was described as severe. Best-corrected visual acuity was limited to light perception.
CaseNotHPOs: HP:0007730 (Iris hypopigmentation)
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
CaseMethod1: Sanger sequencing
CaseMethod2: N/A
CaseGenotypingMethod: Patients were genotyped by Sanger sequencing of PCR products from the 9 exons of the GPR143 gene.
Variant: The proband harbors the NM_000273.3(GPR143):c.333_360+14delinsCTT variant in the hemizygous state.
CAID: CA2573320702
gnomAD: This variant was not found in gnomAD v2.1.1.
VariantEvidence: NM_000273.3(GPR143):c.333_360+14delinsCTT is an indel variant removing the 3' end of exon 2 including the canonical splice donor site, and is predicted to either introduce a premature stop codon or exon skipping.
CaseAddInfo: N/A
CasePMIDs: N/A
c.793C>T (p.R265X)
Case#: Zou_2017_Patient_F3-III:3, male, age 24 at time of report, family national origin reported to be from China
CasePresentingHPOs: HP:0000639 (Nystagmus), HP:0000613 (Photophobia), HP:0007663 (Reduced visual acuity), HP:0007750 (Hypoplasia of the fovea), HP:0007894 (Hypopigmentation of the fundus), HP:0007730 (Iris hypopigmentation), HP:0030534 (Abnormal best corrected visual acuity test)
CaseHPOFreeText: The proband has been diagnosed with ocular albinism 1. Foveal hypoplasia was described as severe. Best-corrected visual acuity was limited to light perception.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: N/A
CaseMethod1: Sanger sequencing
CaseMethod2: N/A
CaseGenotypingMethod: Patients were genotyped by Sanger sequencing of PCR products from the 9 exons of the GPR143 gene.
Variant: The proband harbors the NM_000273.3(GPR143):c.733C>T (p.Arg245Ter) variant in the hemizygous state.
ClinVar: 1352731
gnomAD: This variant was not found in gnomAD v2.1.1.
VariantEvidence: NM_000273.3(GPR143):c.733C>T (p.Arg245Ter) is a nonsense variant in exon 6 of 9, and is predicted to trigger nonsense-mediated decay or to at least truncate the C-terminal 40% of the protein product.
CaseAddInfo: N/A
CasePMIDs: N/A
OA1 mutations and deletions in X-linked ocular albinism.
PMID: 9529334
Gene: GPR143
HGNC: 20145
Disease: X-linked recessive ocular albinism
MONDO: 0021019
InheritancePattern: X-linked recessive
Prevalence: Ocular albinism has an estimated prevalence between 1 in 111,000 and 1 in 1,000,000 live births (PMID: 35495622)
Penetrance: Fully penetrant in males, with onset in infancy. Most female carriers appear to be unaffected.
Mutations in GPR143/OA1 and ABCA4 Inform Interpretations of Short-Wavelength and Near-Infrared Fundus Autofluorescence
PMID: 29847651
Gene: GPR143
HGNC: 20145
Disease: X-linked recessive ocular albinism
MONDO: 0021019
InheritancePattern: X-linked recessive
Prevalence: Ocular albinism has an estimated prevalence between 1 in 111,000 and 1 in 1,000,000 live births (PMID: 35495622)
Penetrance: Fully penetrant in males, with onset in infancy. Most female carriers appear to be unaffected.
P6 (father of P1, P2, P3) was hemizygous for the mutation c.461del_T (p.Ile154fs) in GPR143/OA1 and is described in the Supplement.
Case#: Paavo_2018_Patient_6, male, 43.1 years of age at time of report, family origin reported as Hispanic
CasePresentingHPOs: N/A
CaseHPOFreeText: The proband has been diagnosed with ocular albinism 1.
CaseNotHPOs: N/A
CaseNotHPOFreeText: N/A
CasePreviousTesting: It is not clear whether previous genotyping was performed.
CaseMethod1: Sanger sequencing
CaseMethod2: N/A
CaseGenotypingMethod: The patient's family appears to have been genotyped by Sanger sequencing of the 9 exons from the GPR143 gene.
Variant: The proband harbors the NM_000273.3(GPR143):c.461del (p.Ile154fs) variant in the hemizygous state.
ClinVar: 817370
gnomAD: This variant was not found in gnomAD v2.1.1.
VariantEvidence: NM_000273.3(GPR143):c.461del (p.Ile154fs) is a frameshift variant in exon 4 of 9, and is predicted to trigger nonsense-mediated decay or to at least truncate the C-terminal 62% of the protein product.
CaseAddInfo: The proband has three daughters who carry the variant in the heterozygous state but are reportedly unaffected, other than one daughter reporting difficulty seeing in the dark.
CasePMIDs: N/A
Cardiovascular actions of DOPA mediated by the gene product of ocular albinism 1
PMID: 25185585
Gene: GPR143
HGNC: 20145
Disease: X-linked recessive ocular albinism
MONDO: 0021019
InheritancePattern: X-linked recessive
Prevalence: Ocular albinism has an estimated prevalence between 1 in 111,000 and 1 in 1,000,000 live births (PMID: 35495622)
Penetrance: Fully penetrant in males, with onset in infancy. Most female carriers appear to be unaffected.
Iris hyperpigmentation in a Chinese family with ocular albinism and the GPR143 mutation
PMID: 19610097
Gene: GPR143
HGNC: 20145
Disease: X-linked recessive ocular albinism
MONDO: 0021019
InheritancePattern: X-linked recessive
Prevalence: Ocular albinism has an estimated prevalence between 1 in 111,000 and 1 in 1,000,000 live births (PMID: 35495622)
Penetrance: Fully penetrant in males, with onset in infancy. Most female carriers appear to be unaffected.
Ocular albinism: evidence for a defect in an intracellular signal transduction system
PMID: 10471510
Gene: GPR143
HGNC: 20145
Disease: X-linked recessive ocular albinism
MONDO: 0021019
InheritancePattern: X-linked recessive
Prevalence: Ocular albinism has an estimated prevalence between 1 in 111,000 and 1 in 1,000,000 live births (PMID: 35495622)
Penetrance: Fully penetrant in males, with onset in infancy. Most female carriers appear to be unaffected.
We provide here structural evidence that the protein product of the ocular albinism type 1 gene (OA1), a pigment cell-specific integral membrane glycoprotein, represents a novel member of the GPCR superfamily and demonstrate that it binds heterotrimeric G proteins. Moreover, we show that OA1 is not found at the plasma membrane, being instead targeted to specialized intracellular organelles, the melanosomes. Our data suggest that OA1 represents the first example of an exclusively intracellular GPCR
Selection B- Gene function is consistent with phenotype.
Title: GPR143 binds heterotrimeric G proteins and shows subcellular localization to melanosomes.
GOterm: GO:0032402 (melanosome transport)
FunctionalEvidence: Exogenously expressed GPR143 in COS-7 cells forms protein-protein interactions with heterotrimeric G-proteins that can be co-immunoprecipitated (Figure 2). This was validated with endogenous GPR143 (Figure 3). GPR143 shows subcellular localization not to the plasma membrane but to melanosomes (Figures 4, 6).
FunctionalHPO: HP:0005592 (Giant melanosomes in melanocytes), severely reduced microtubule-based motility in melanosomes
HumanPhenotype: HP:0005592 (Giant melanosomes in melanocytes), HP:0007894 (Hypopigmentation of the fundus), severely reduced microtubule-based motility in melanosomes, Giant melanosomes in retinal pigment epithelial cells
PhenotypeEvidence: This evidence is consistent with the melanocyte trafficking defects characteristic of human patients.
The ocular albinism type 1 protein, an intracellular G protein-coupled receptor, regulates melanosome transport in pigment cells
PMID: 18697795
Gene: GPR143
HGNC: 20145
Disease: X-linked recessive ocular albinism
MONDO: 0021019
InheritancePattern: X-linked recessive
Prevalence: Ocular albinism has an estimated prevalence between 1 in 111,000 and 1 in 1,000,000 live births (PMID: 35495622)
Penetrance: Fully penetrant in males, with onset in infancy. Most female carriers appear to be unaffected.
We report here the identification of an unexpected abnormality in melanosome distribution both in retinal pigment epithelium (RPE) and skin melanocytes of Oa1-knock-out (KO) mice, consisting in a displacement of the organelles from the central cytoplasm towards the cell periphery. Despite their depletion from the microtubule (MT)-enriched perinuclear region, Oa1-KO melanosomes were able to aggregate at the centrosome upon disruption of the actin cytoskeleton or expression of a dominant-negative construct of myosin Va. Consistently, quantification of organelle transport in living cells revealed that Oa1-KO melanosomes displayed a severe reduction in MT-based motility; however, this defect was rescued to normal following inhibition of actin-dependent capture at the cell periphery. Together, these data point to a defective regulation of organelle transport in the absence of OA1 and imply that the cytoskeleton might represent a downstream effector of this receptor. Furthermore, our results enlighten a novel function for OA1 in pigment cells and suggest that ocular albinism type 1 might result from a different pathogenetic mechanism than previously thought, based on an organelle-autonomous signalling pathway implicated in the regulation of both membrane traffic and transport.
ExperimentName: Continued studies of mouse model with hemizygous disruption of the GPR143 ortholog Oa1
NonHumanModel: Mus musculus
GeneAlteration: A hemizygous mouse model of Oa1 knockout was previously generated by replacement of exon 1 (including the start codon) with a cassette to facilitate selection (PMID: 11092754).
ModelPhenotype: HP:0003593 (Infantile onset), HP:0005592 (Giant melanosomes in melanocytes), severely reduced microtubule-based motility in melanosomes
HumanPhenotype: HP:0000639 (Nystagmus), HP:0003593 (Infantile onset), HP:0007663 (Reduced visual acuity), HP:0001361 (Nystagmus-induced head nodding), HP:0000646 (Amblyopia), HP:0000483 (Astigmatism), HP:0000613 (Photophobia), normally pigmented skin and hair, HP:0005592 (Giant melanosomes in melanocytes), HP:0007750 (Hypoplasia of the fovea), HP:0007894 (Hypopigmentation of the fundus), HP:0025551 (Optic nerve misrouting)
ModelEvidence: The mice match the human patients in that they exhibit congenital onset of cytological abnormalities (PMID: 16303920), These were previously shown in the RPE and are here shown in the melanocytes as well (Figure 3). Most importantly, this study shows a defect in microtubule-based melanosome motility (Figure 7), indicating an underlying mechanism for the disease.
ModelVariant: This model features disruption of Oa1 by knockout, but does not harbor a mutation equivalent to a variant from a human patient.
Interaction between G-coupled Protein Receptor 143 and tyrosinase: Implications for understanding Ocular Albinism Type-1
PMID: 27720922
Gene: GPR143
HGNC: 20145
Disease: X-linked recessive ocular albinism
MONDO: 0021019
InheritancePattern: X-linked recessive
Prevalence: Ocular albinism has an estimated prevalence between 1 in 111,000 and 1 in 1,000,000 live births (PMID: 35495622)
Penetrance: Fully penetrant in males, with onset in infancy. Most female carriers appear to be unaffected.
We therefore investigated potential GPR143 interaction partners, with a focus on the melanogenic enzyme tyrosinase. GPR143 co-immunoprecipitated with tyrosinase, while confocal microscopy demonstrated colocalization of the proteins. Furthermore, tyrosinase localized to the plasma membrane when co-expressed with a GPR143 trafficking mutant. The physical interaction between the proteins was confirmed using Fluorescence Resonance Energy Transfer.
ExperimentName: GPR143 interacts with TYR by co-IP and FRET
InteractingGene: TYR, which is implicated in oculocutaneous albinism types 1A and 1B
InteractionType: Physical
InteractionMethod: Co-immunoprecipitation and FRET were both performed with positive results.
InteractionEvidence: Co-IP of the exogenously expressed GPR143 fusion protein or endogenous TYR found that IP of one protein pulls down the other as well (Figure 2). This was confirmed by fluorescent resonance energy transfer experiments (Figures 4 and 5). Use of a mislocalizing GPR143 mutant control showed that TYR localization appears to be GPR143-dependent (Figures 3 and 4).
In this study, we have generated and characterized Oa1-deficient mice by gene targeting (KO). The KO males are viable, fertile and phenotypically indistinguishable from the wild-type littermates. Ophthalmologic examination shows hypopigmentation of the ocular fundus in mutant animals compared with wild-type. Analysis of the retinofugal pathway reveals a reduction in the size of the uncrossed pathway, demonstrating a misrouting of the optic fibres at the chiasm, as observed in OA1 patients. Microscopic examination of the RPE shows the presence of giant melanosomes comparable with those described in OA1 patients. Ultrastructural analysis of the RPE cells, suggests that the giant melanosomes may form by abnormal growth of single melanosomes, rather than the fusion of several, shedding light on the pathogenesis of ocular albinism.
ExperimentName: Mouse model with hemizygous disruption of the GPR143 ortholog Oa1
NonHumanModel: Mus musculus
GeneAlteration: A hemizygous mouse model of Oa1 knockout was generated by replacement of exon 1 (including the start codon) with a cassette to facilitate selection.
ModelPhenotype: HP:0007894 (Hypopigmentation of the fundus), HP:0025551 (Optic nerve misrouting), Giant melanosomes in retinal pigment epithelial cells
HumanPhenotype: HP:0000639 (Nystagmus), HP:0003593 (Infantile onset), HP:0007663 (Reduced visual acuity), HP:0001361 (Nystagmus-induced head nodding), HP:0000646 (Amblyopia), HP:0000483 (Astigmatism), HP:0000613 (Photophobia), normally pigmented skin and hair, HP:0005592 (Giant melanosomes in melanocytes), HP:0007750 (Hypoplasia of the fovea), HP:0007894 (Hypopigmentation of the fundus), HP:0025551 (Optic nerve misrouting)
ModelEvidence: Although the coat, eye color, and ERG responses of the mice were unaffected, the mice match the human patients in that they exhibit hypopigmentation of the fundus (Fig. 2), optic fiber misrouting at the chiasm, and expansion of individual melanosomes into giant melanosomes within cells of the RPE (Figures 2, 3). The mice match the mode of inheritance from the human patients.
ModelVariant: This model features disruption of Oa1 by knockout, but does not harbor a mutation equivalent to a variant from a human patient.
Oa1 knock-out: new insights on the pathogenesis of ocular albinism type 1
PMID: 11092754
Gene: GPR143
HGNC: 20145
Disease: X-linked recessive ocular albinism
MONDO: 0021019
InheritancePattern: X-linked recessive
Prevalence: Ocular albinism has an estimated prevalence between 1 in 111,000 and 1 in 1,000,000 live births (PMID: 35495622)
Penetrance: Fully penetrant in males, with onset in infancy. Most female carriers appear to be unaffected.
Identification of three novel OA1 gene mutations identified in three families misdiagnosed with congenital nystagmus and carrier status determination by real-time quantitative PCR assay
PMID: 12515581
Gene: GPR143
HGNC: 20145
Disease: X-linked recessive ocular albinism
MONDO: 0021019
InheritancePattern: X-linked recessive
Prevalence: Ocular albinism has an estimated prevalence between 1 in 111,000 and 1 in 1,000,000 live births (PMID: 35495622)
Penetrance: Fully penetrant in males, with onset in infancy. Most female carriers appear to be unaffected.
In the index patient (IV1) of family OA1-3 that did not show exon deletion, sequence analysis of all coding exons including the exon-intron boundaries revealed a deletion of a single nucleotide G at position 310 of the cDNA introducing a subsequent premature stop codon one codon downstream, predicting a deleterious protein product. This newly described mutation (310delG) in exon 2 of the OA1 gene creates a TaqI restriction site. Although the pedigree of family OAI-3 initially suggested the patient IV1 to be a sporadic case, PCR-restriction analysis identified the patient's maternal uncle (III3), known to have only a decreased visual acuity at age 38, as hemizygous for the mutation. The mother (III2) and the maternal grand-mother (II1) of the proband were found to be carriers (Fig. (Fig.4B),4B), as expected
Case#: Faugere_2003_Family_OA1-3_Patient_IV1, male, 26 years of age at time of report, family origin reported to be from the South of France with race described as Caucasian
CasePresentingHPOs: HP:0006934 (Congenital nystagmus), HP:0007750 (Hypoplasia of the fovea), HP:0007663 (Reduced visual acuity), HP:0001089 (Iris atrophy), HP:0012805 (Iris transillumination defect), HP:0007894 (Hypopigmentation of the fundus), HP:0030602 (Abnormal fundus autofluorescence imaging), HP:0030479 (Abnormal amplitude of light-adapted flicker electroretinogram)
CaseHPOFreeText: The proband was initially diagnosed with congenital nystagmus.
CaseNotHPOs: HP:0012632 (Abnormal intraocular pressure), HP:0000518 (Cataract)
CaseNotHPOFreeText: N/A
CasePreviousTesting: Previous testing was not described, however, the proband was examined for whole-exon deletions using PCR amplification of the 9 exons from the GPR143 locus.
CaseMethod1: Sanger sequencing
CaseMethod2: Restriction enzyme analysis using TaqI
CaseGenotypingMethod: The proband was examined for whole-exon deletions using PCR amplification of the 9 exons from the GPR143 locus, followed by Sanger-based sequencing and restriction enzyme-based screening of family members using TaqI.
Variant: The proband harbors the NM_000273.3(GPR143):c.310del (p.Asp104fs) variant in the hemizygous state.
ClinVar: 98625
gnomAD: This variant was not found in gnomAD v2.1.1.
VariantEvidence: NM_000273.3(GPR143):c.310del (p.Asp104fs) is a frameshift variant in exon 2 of 9, and is predicted to trigger nonsense-mediated decay or to at least truncate the C-terminal 75% of the protein product.
CaseAddInfo: While the proband was initially thought to be a sporadic case, the variant was later found to be maternally inherited, with an uncle found to harbor the variant and to be affected with decreased visual acuity. Further details of the family member are not described.
CasePMIDs: N/A
Deletion in the OA1 gene in a family with congenital X linked nystagmus
PMID: 11520764
Gene: GPR143
HGNC: 20145
Disease: X-linked recessive ocular albinism
MONDO: 0021019
InheritancePattern: X-linked recessive
Prevalence: Ocular albinism has an estimated prevalence between 1 in 111,000 and 1 in 1,000,000 live births (PMID: 35495622)
Penetrance: Fully penetrant in males, with onset in infancy. Most female carriers appear to be unaffected.
Case#: Preising_2001_Patient_IV.1, male, age 3 months at time of diagnosis, family ethnicity described as White
CasePresentingHPOs: HP:0006934 (Congenital nystagmus), HP:0012805 (Iris transillumination defect), HP:0007894 (Hypopigmentation of the fundus), HP:0001104 (Macular hypoplasia), HP:0007663 (Reduced visual acuity), HP:0030463 (Asymmetrical distribution of flash visual evoked potentials), HP:0025551 (Optic nerve misrouting)
CaseHPOFreeText: The proband and his family members have been diagnosed with congenital nystagmus.
CaseNotHPOs: HP:0009887 (Abnormality of hair pigmentation), HP:0001000 (Abnormality of skin pigmentation)
CaseNotHPOFreeText: N/A
CasePreviousTesting: The patients were initially genotyped by SSCP of PCR products from each exon, revealing an abnormality in exon 6.
CaseMethod1: SSCP
CaseMethod2: Sanger sequencing
CaseGenotypingMethod: The proband was initially genotyped by SSCP of PCR products from each exon, revealing an abnormality in exon 6, followed by Sanger sequencing and restriction enzyme analysis by Tsp509I digest of PCR products from all family members.
Variant: The proband harbors the NM_000273.3(GPR143):c.756_767+2del variant in the hemizygous state.
ClinVar: 98643
gnomAD: This variant was not found in gnomAD v2.1.1.
VariantEvidence: NM_000273.3(GPR143):c.756_767+2del is a 14-bp deletion variant removing the 3' end of exon 6 and the canonical splice donor site, and has been shown to trigger aberrant splicing that leads to frameshift at codon 252 and premature termination at codon 259 (Figure 4C).
CaseAddInfo: The proband is part of a family with at least 3 affected generations showing a pattern of X-linked inheritance, including a similarly affected maternal uncle.
CasePMIDs: N/A
Novel GPR143 mutations and clinical characteristics in six Chinese families with X-linked ocular albinism
PMID: 18978956
Gene: GPR143
HGNC: 20145
Disease: X-linked recessive ocular albinism
MONDO: 0021019
InheritancePattern: X-linked recessive
Prevalence: Ocular albinism has an estimated prevalence between 1 in 111,000 and 1 in 1,000,000 live births (PMID: 35495622)
Penetrance: Fully penetrant in males, with onset in infancy. Most female carriers appear to be unaffected.
c.849delT (p.Val284SerfsX15)
Case#: Fang_2008_Family_1_Patient_IV16, male, age 8 at time of report, family national origin reported to be from China
CasePresentingHPOs: HP:0000639 (Nystagmus), HP:0030534 (Abnormal best corrected visual acuity test), HP:0007750 (Hypoplasia of the fovea)
CaseHPOFreeText: The proband and his affected family members have been diagnosed with ocular albinism 1.
CaseNotHPOs: HP:0007730 (Iris hypopigmentation), HP:0007894 (Hypopigmentation of the fundus)
CaseNotHPOFreeText: albinotic fundus
CasePreviousTesting: N/A
CaseMethod1: Sanger sequencing
CaseMethod2: N/A
CaseGenotypingMethod: The proband was genotyped by Sanger sequencing of PCR products from the 9 exons of the GPR143 gene.
Variant: The proband harbors the NM_000273.3(GPR143):c.849del (p.Val284SerfsTer15) variant in the hemizygous state.
CAID: CA2573320706
gnomAD: This variant was not found in gnomAD v2.1.1.
VariantEvidence: NM_000273.3(GPR143):c.849del (p.Val284SerfsTer15) is a frameshift variant in exon 7 of 9, predicted to trigger nonsense-mediated decay or to at least truncate 30% of the protein product.
CaseAddInfo: The family of the proband includes at least 7 other affected males and 4 unaffected female carriers.
CasePMIDs: N/A
Morpholino-mediated knockdown of OA1 (also known as GPR143), mutations in the human homologue of which cause the most common form of human ocular albinism, induces a major reduction in melanosome number, recapitulating a key feature of the mammalian disease where reduced melanosome numbers precede macromelanosome formation.
ExperimentName: Zebrafish knockdown of the GPR143 ortholog OA1
NonHumanModel: Danio rerio
GeneAlteration: A zebrafish model of OA1 loss-of-function was generated by morpholino-based knockdown.
ModelPhenotype: HP:0007703 (Abnormality of retinal pigmentation)
HumanPhenotype: HP:0000639 (Nystagmus), HP:0003593 (Infantile onset), HP:0007663 (Reduced visual acuity), HP:0001361 (Nystagmus-induced head nodding), HP:0000646 (Amblyopia), HP:0000483 (Astigmatism), HP:0000613 (Photophobia), normally pigmented skin and hair, HP:0005592 (Giant melanosomes in melanocytes), HP:0007750 (Hypoplasia of the fovea), HP:0007894 (Hypopigmentation of the fundus), HP:0025551 (Optic nerve misrouting)
ModelEvidence: The zebrafish match one feature of the human patients in that they exhibit abnormalities of retinal pigmentation consistent with the ability of GPR143 loss-of-function to trigger defects in melanosome regulation (Figure 1).
ModelVariant: This model features disruption of OA1 expression by knockdown, and does not harbor a mutation equivalent to a variant from a human patient.
Regulation of melanosome number, shape and movement in the zebrafish retinal pigment epithelium by OA1 and PMEL
PMID: 25690007
Gene: GPR143
HGNC: 20145
Disease: X-linked recessive ocular albinism
MONDO: 0021019
InheritancePattern: X-linked recessive
Prevalence: Ocular albinism has an estimated prevalence between 1 in 111,000 and 1 in 1,000,000 live births (PMID: 35495622)
Penetrance: Fully penetrant in males, with onset in infancy. Most female carriers appear to be unaffected.
Clinical features of affected males with X linked ocular albinism
PMID: 8494858
Gene: GPR143
HGNC: 20145
Disease: X-linked recessive ocular albinism
MONDO: 0021019
InheritancePattern: X-linked recessive
Prevalence: Ocular albinism has an estimated prevalence between 1 in 111,000 and 1 in 1,000,000 live births (PMID: 35495622)
Penetrance: Fully penetrant in males, with onset in infancy. Most female carriers appear to be unaffected.
Localization of the X-linked ocular albinism gene (OA1) between DXS278/DXS237 and DXS143/DXS16 by linkage analysis
PMID: 2280973
Gene: GPR143
HGNC: 20145
Disease: X-linked recessive ocular albinism
MONDO: 0021019
InheritancePattern: X-linked recessive
Prevalence: Ocular albinism has an estimated prevalence between 1 in 111,000 and 1 in 1,000,000 live births (PMID: 35495622)
Penetrance: Fully penetrant in males, with onset in infancy. Most female carriers appear to be unaffected.
Identification of a novel GPR143 deletion in a Chinese family with X-linked congenital nystagmus
PMID: 18523664
Gene: GPR143
HGNC: 20145
Disease: X-linked recessive ocular albinism
MONDO: 0021019
InheritancePattern: X-linked recessive
Prevalence: Ocular albinism has an estimated prevalence between 1 in 111,000 and 1 in 1,000,000 live births (PMID: 35495622)
Penetrance: Fully penetrant in males, with onset in infancy. Most female carriers appear to be unaffected.
In this study, we collected data from a four-generation Chinese family with X-linked congenital nystagmus. All the affected individuals suffer from nystagmus and amblyopia but without any sign of retinal hypopigmentation. We mapped the disease-causing gene to Xp22.3 and found a 37-bp deletion in exon 1 of GPR143 in all affected male and female carriers.
Case#: Zhou_2008_Patient_III:22, male, age of onset not reported, family origin reported to be from China
CasePresentingHPOs: HP:0000639 (Nystagmus), HP:0000646 (Amblyopia)
CaseHPOFreeText: The proband has been diagnosed with congenital nystagmus.
CaseNotHPOs: HP:0040030 (Chorioretinal hypopigmentation)
CaseNotHPOFreeText: N/A
CasePreviousTesting: Genotyping was initially performed by linkage mapping using 26 short tandem repeat markers on the X chromosome.
CaseMethod1: linkage analysis
CaseMethod2: Sanger sequencing
CaseGenotypingMethod: Genotyping was initially performed by linkage mapping using 26 short tandem repeat markers on the X chromosome, followed by Sanger sequencing of PCR products from each exon of the GPR143 gene.
Variant: The proband harbors the NM_000273.3(GPR143):c.162_198del (p.Ala55fs) variant in the hemizygous state.
ClinVar: 10524
gnomAD: This variant was not found in gnomAD v2.1.1.
VariantEvidence: NM_000273.3(GPR143):c.162_198del (p.Ala55fs) is a frameshift variant in exon 1, and is predicted to trigger nonsense-mediated decay or to at least truncate the C-terminal 87% of the protein product.
CaseAddInfo: The proband is from a family with at least seven other affected males who also harbor the variant.
CasePMIDs: N/A