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A recurrent de novo missense mutation in UBTF causes developmental neuroregression.

ABSTRACT: UBTF (upstream binding transcription factor) exists as two isoforms; UBTF1 regulates rRNA transcription by RNA polymerase 1, whereas UBTF2 regulates mRNA transcription by RNA polymerase 2. Herein, we describe 4 patients with very similar patterns of neuroregression due to recurrent de novo mutations in UBTF (GRCh37/hg19, NC_000017.10: g.42290219C?>?T, NM_014233.3: c.628G?>?A) resulting in the same amino acid change in both UBTF1 and UBTF2 (p.Glu210Lys [p.E210K]). Disease onset in our cohort was at 2.5 to 3 years and characterized by slow progression of global motor, cognitive and behavioral dysfunction. Notable early features included hypotonia with a floppy gait, high-pitched dysarthria and hyperactivity. Later features included aphasia, dystonia, and spasticity. Speech and ambulatory ability were lost by the early teens. Magnetic resonance imaging showed progressive generalized cerebral atrophy (supratentorial?>?infratentorial) with involvement of both gray and white matter. Patient fibroblasts showed normal levels of UBTF transcripts, increased expression of pre-rRNA and 18S rRNA, nucleolar abnormalities, markedly increased numbers of DNA breaks, defective cell-cycle progression, and apoptosis. Expression of mutant human UBTF1 in Drosophila neurons was lethal. Although no loss-of-function variants are reported in the Exome Aggregation Consortium (ExAC) database and Ubtf-/- is early embryonic lethal in mice, Ubtf+/- mice displayed only mild motor and behavioral dysfunction in adulthood. Our data underscore the importance of including UBTF E210K in the differential diagnosis of neuroregression and suggest that mainly gain-of-function mechanisms contribute to the pathogenesis of the UBTF E210K neuroregression syndrome.

SUBMITTER: Toro C

PROVIDER: S-EPMC5886272 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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Project description:Surveillance for bovine genetic diseases in Denmark identified a hitherto unreported congenital syndrome occurring among progeny of a Holstein sire used for artificial breeding. A genetic aetiology due to a dominant inheritance with incomplete penetrance or a mosaic germline mutation was suspected as all recorded cases were progeny of the same sire. Detailed investigations were performed to characterize the syndrome and to reveal its cause.Seven malformed calves were submitted examination. All cases shared a common morphology with the most striking lesions being severe facial dysplasia and complete prolapse of the eyes. Consequently the syndrome was named facial dysplasia syndrome (FDS). Furthermore, extensive brain malformations, including microencephaly, hydrocephalus, lobation of the cerebral hemispheres and compression of the brain were present. Subsequent data analysis of progeny of the sire revealed that around 0.5% of his offspring suffered from FDS. High density single nucleotide polymorphism (SNP) genotyping data of the seven cases and their parents were used to map the defect in the bovine genome. Significant genetic linkage was obtained for three regions, including chromosome 26 where whole genome sequencing of a case-parent trio revealed two de novo variants perfectly associated with the disease: an intronic SNP in the DMBT1 gene and a single non-synonymous variant in the FGFR2 gene. This FGFR2 missense variant (c.927G>T) affects a gene encoding a member of the fibroblast growth factor receptor family, where amino acid sequence is highly conserved between members and across species. It is predicted to change an evolutionary conserved tryptophan into a cysteine residue (p.Trp309Cys). Both variant alleles were proven to result from de novo mutation events in the germline of the sire.FDS is a novel genetic disorder of Holstein cattle. Mutations in the human FGFR2 gene are associated with various dominant inherited craniofacial dysostosis syndromes. Given the phenotypic similarities in FDS affected calves, the genetic mapping and absence of further high impact variants in the critical genome regions, it is highly likely that the missense mutation in the FGFR2 gene caused the FDS phenotype in a dominant mode of inheritance.

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A recurrent de novo missense mutation in UBTF causes developmental neuroregression.

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