Nb 60 M – c.768C>G p.S256R + + + + Spasticity c.854A>G p.Q285R Ob 64 F – c.768C>G p.S256R + + + + Spasticity c.854A>G p.Q285R
The individuals mentioned are from a previous publication (PMID: 20157015) which has already been included in the VCI. But may add cell line data demonstrating mitochondrial dysfunction and increasing PP4 to moderate.
a 60-year-old man and his 64-year-old sister (p.[S256R];[Q285R]), who both show ataxia, myopathy, peripheral neuropathy, and spasticity in addition to optic atrophy [42],
This variant is mentioned as a reference to a previous publication (PMID: 20157015) which has already been included in the VCI.
Yu-Wai-Man et al. [6] unknown M c.768C>G/p.Ser256Arg c.854A>G/p.Gln285Arg Unk Yes Yes Yes Not reported unknown unknown
This variant is mentioned as a reference to a previous publication (PMID: 20157015) which has already been included in the VCI.
NO-1 60 M + + + + + Spasticity c.768C>G p.S256R CC c.854A>G p.Q285R GTPase
Case#: Family NO-1, 60yo, male, Norwegian
DiseaseAssertion: DOA+
FamilyInfo: positive family history: affected sister with same genotype, 2 unaffected daughters with only the c.768C>G p.S256R variant. Parents are deceased but were apparently healthy
CasePresentingHPOs: HP:0000648, HP:0001251, HP:0003198, HP:0009830, HP:0001257
CaseHPOFreeText: corticospinal tract involvement
CaseNotHPOs:
CaseNotHPOFreeText:
PreviouslyPublished: n/a
GenotypingMethod: The entire OPA1-coding region and flanking exon–intron boundaries were amplified by the polymerase chain reaction (PCR) and sequenced with BigDye terminator cycle chemistries on an appropriate genetic analyser. All genetic variants were confirmed by reverse sequencing. Initial screens for POLG1, POLG2, PEO1 and SLC25A4 were found to be negative,
Variant: c.768C > G (p.S256R) and c.854A > G (p.Q285R), confirmed in trans by haplotype analysis
CAID: CA355787228
SupplementalData: n/a
This observation was consistent with the reduced OPA1 protein levels observed in another patient (NO-1) with a complicated syndromic DOA phenotype characterised by optic atrophy and marked generalised neurodegenerative features, who has been confirmed to harbour compound heterozygous OPA1 missense mutations in exon 5b (c.768C>G, p.Ser256Arg) and exon 8 (c.854A>G, p.Gln285Arg; figure 1C).
Western blot of the variant in the proband NO-1 from previously published PMID: 20157015
As Bonneau et al. (2014) correctly point out, we did describe two siblings from a non-consanguineous Norwegian family in our original Brain paper, who developed a particularly aggressive disease course characterized by ataxia, spasticity, peripheral neuropathy and myopathy (Yu-Wai-Man et al., 2010). OPA1 sequencing identified two pathogenic variants in both the affected brother and sister: the c.768C>G (p.Ser256Arg) missense mutation in exon 5b and the c.854A>G (p.Gln285Arg) missense mutation in exon 8. Bonneau et al. (2014) rightly queried whether we had actually proven compound heterozygosity in these two affected Norwegian siblings. Although DNA was not available from their deceased parents, we did have access to DNA samples from the brother’s two unaffected daughters and both harboured only the c.768C>G (p.Ser256Arg) substitution in exon 5b. Furthermore, haplotype analysis provided additional evidence that the proband and his affected sister were indeed compound heterozygous for the c.768C>G (p.Ser256Arg) and the c.854A>G (p.Gln285Arg) OPA1 mutations (Yu-Wai-Man et al., 2010).
This variant is mentioned as a reference to a previous publication (PMID: 20157015) which has already been included in the VCI.