Novel gene PUS3 c.A212G mutation in Ukrainian family with intellectual disability

Abstract

To evaluate a possible role of a novel c.A212G substitution in the PUS3 gene at intellectual disability (ID). Methods. The observed group consisted of the ID Ukrainian family members (parents and two affected children) and the control group-of 300 healthy individuals from general population of Ukraine. Sanger sequencing of the PUS3 gene exon 1 was performed for the family members. Polymorphic variants of c.A212G were analyzed using ARMS PCR. The homology models of wild type and p.Y71C mutant catalytic domains of human Pus3 were generated using the crystal structure of the human Pus1 catalytic domain (PDB ID: 4NZ6) as a template. Results. It was shown that the father of the affected siblings was the c.A212G substitution heterozygous carrier whereas the mother was a wild type allele homozygote, and the exom sequencing result was confi rmed-the affected children are 212G homozygotes. We supposed de novo mutation in the maternal germ line. A low frequency of 212G allele (0.0017) was shown in the population of Ukraine. Homology modelling of the wild type and p.Y71C mutant catalytic domain of human Pus3 revealed that substitution p.Y71C is located in close proximity to its active site. Conclusions. The absence of hypoproteinemia in our patients, homozygous for the 212C allele allows us to assume that the mutation c.A212G PUS3 is rather neutral and cannot be the major cause of ID. However, considering a low frequency of the 212G allele in the population and close localization of p.Y71C substitution to the active site of hPus3 we cannot exclude that the c.A212G mutation in PUS3 may be a modifi er for some pathologies including syndromic ID.

Association of the EPHA1 gene polymorphism with idiopathic mild intellectual disability

“…Polymorphic variants c.1475G > A (rs11768549) and c.1891G > A (novel) of EPHA1 gene were detected as described in our recent work [2].…”

“…In recent reports we have presented our study on the whole exome sequencing (WES) in two affected siblings with non-syndromic intellectual disability from Ukrainian family and their healthy non-consanguineous parents that identifi ed two missense mutations in the coding region of the EPHA1 gene (c. 1475 G > A -rs11768549 and novel c.1891G > A) [1][2][3].…”

Clinical and molecular delineation of PUS3‐associated neurodevelopmental disorders

“…Clinical information of two previously reported brothers (Family G, individuals 8,9) were updated. 15 The clinical features of all the unpublished, updated, and published individuals are included in Eight of the individuals had a height ≤ 3rd percentile, two individuals were described as short, and two further individuals had a stature on the 10th percentile.…”

“…Seven previously unpublished individuals from six families were ascertained through GeneMatcher (https://genematcher.org/statistics) or other ongoing collaborations (individuals 1–7), and clinical examination was carried out by the local clinicians (Table 1 and Table S1). Clinical information of two previously reported brothers (Family G, individuals 8,9) were updated 15 . The clinical features of all the unpublished, updated, and published individuals are included in Table S1.…”

“…Impairment of proteins involved in tRNA biogenesis, including tRNA modification, has an impact on cognition and brain development, 7 and PUS3 is one of the proteins of the RNA biogenesis which is linked to a neurodevelopmental disorder 8 . To date 14 individuals (from nine families) have been reported exhibiting either compound heterozygous or homozygous variants in PUS3 8–16 . The clinical manifestations of the disorder range from moderate to more severe phenotypes, including ID, epilepsy, microcephaly, nonspecific facial dysmorphism and neuropsychiatric disorders.…”