ClinVar Genomic variation as it relates to human health

Dystonic disorder (present) , Global developmental delay (present) , Hypotonia (present) , Myoclonus (present) , Strabismus (present) , Abnormal cerebral ventricle morphology (present) , Axial hypotonia (present) (less)

In 11 affected children from 5 consanguineous Turkish families with pontocerebellar hypoplasia (PCH10; 615803), Karaca et al. (2014) identified a homozygous c.419G-A transition in the CLP1 gene, resulting in an arg140-to-his (R140H) substitution at a highly conserved residue. The mutation, which was found in the first 2 families by whole-exome sequencing, was not present in the 1000 Genomes Project or Exome Variant Server databases or in 2,500 in-house control exomes. The mutation was identified by Sanger sequencing and segregated with the disorder in 3 additional families with a similar phenotype. Haplotype analysis indicated a founder effect for the 5 families. In vitro functional expression assays in E. coli showed that the R140H mutant protein retained some RNA kinase activity, but did not interact with other members of the tRNA splicing endonuclease (TSEN) complex, resulting in decreased pre-tRNA cleavage activity and abnormal cellular accumulation of linear tRNA introns, although pre- and mature tRNA levels were largely unaffected. Patient cultured fibroblasts showed decreased RNA kinase activity and only minor detectable pre-tRNA cleavage activity. Simultaneously and independently, Schaffer et al. (2014) identified a homozygous R140H mutation in affected members of 4 consanguineous Turkish families with PCH10. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families and was not present in public databases. It was observed twice in heterozygosity among more than 2,000 in-house exomes, yielding a carrier frequency of 1:1,100. Haplotype analysis indicated a founder effect. Recombinant R140H CLP1 showed defective kinase activity that was reduced by more than half of wildtype levels. Induced neurons derived from patient fibroblasts showed reduced nuclear localization of mutant CLP1, also suggesting impaired function. Northern blot analysis identified accumulation of pre-tRNAs and depletion of mature tRNAs specifically in patient-induced neurons. These abnormalities were associated with loss of CLP1 affinity for the TSEN complex and with impaired pre-tRNA cleavage activity. Patient cells showed increased sensitivity to oxidative stress-induced death exacerbated by the addition of unphosphorylated 3-prime-tRNA exon halves. In 2 distantly related girls (proband and her first cousin once removed) from a Turkish family with PCH10, Wafik et al. (2018) identified homozygosity for the founder R140H mutation in the CLP1 gene. The mutation was found by trio-based whole-exome sequencing and confirmed by Sanger sequencing. Both sets of parents were heterozygous for the mutation. (less)