Spondyloepimetaphyseal dysplasia with neurodegeneration associated with AIFM1 mutation a novel phenotype of the mitochondrial disease

ABSTRACT

In 1999, based on a single family, spondyloepimetaphyseal dysplasia (SEMD) with mental retardation (MR) was described as a novel syndrome with likely X-linked recessive inheritance and unknown molecular defect (MIM 300232). Our purpose was to search for the causative defect in the originally described family and in an independently ascertained second family. All patients had slowly progressive neurodegeneration with central and peripheral involvement and identical skeletal dysplasia. Whole exome sequencing performed in two subjects showed a single plausible candidate – the p.Asp237Gly variant in AIFM1 (chr. Xq26.1). The p.Asp237Gly segregated with disease as indicated by linkage analysis (maximum lod score at theta 0 for the two families was 3.359). This variant had not been previously reported and it was predicted to be pathogenic by Polyphen2, SIFT, MutationTaster and Mutation Assessor. AIFM1 encodes mitochondria associated apoptosis inducing factor. The AIFM1 gene has been linked with COXPD6 encephalomyopathy (MIM 300816), Cowchock syndrome (MIM 310490) and X-linked deafness with neuropathy (DFNX5, MIM 300614), none of which are similar to SEMD-MR. Our results place SEMD as the third instance of a skeletal phenotype associated with a mitochondrial disease (the others being EVEN-PLUS syndrome caused by mutations of HSPA9 and CODAS syndrome due to LONP1 mutations).

Pedigrees of SEMD-MD families White arrows – subjects studied by WES AIFM1: p.Asp237Gly status: −/− wild-type female, +/− female carrier, −/ wild-type hemizygous male, +/ male with hemizygous mutation

AIFM1 domain structure showing p.D237G (black) and mutations previously associated with other diseases (DFNX5 –green, Cowchock syndrome – blue, COXPD6 -pink)

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