Homozygous splice mutation in CWF19L1 in a Turkish family with recessive ataxia syndrome

Abstract

Objective: To elucidate the genetic cause of a rare recessive ataxia presented by 2 siblings from a consanguineous Turkish family with a nonprogressive, congenital ataxia with mental retardation of unknown etiology.Methods: Whole-exome sequencing was combined with homozygosity mapping, linkage, and expression analysis to identify candidate genes, confirmed by Sanger sequencing. Reverse transcription-PCR and immunoblotting were used to determine the functional consequences of the gene variant. A zebrafish model was developed using morpholino-mediated knockdown.Results: We identified a homozygous mutation at the invariant 11 position (c.96411G.A) in intron 9 of the CWF19L1 (complexed with cdc5 protein 19-like 1) gene. This mutation is absent in .6,500 European and African American individuals and 200 Turkish control DNAs. The mutation causes exon skipping, reduction in messenger RNA levels, and protein loss in cell lines of affected individuals. Morpholino-mediated knockdown in a zebrafish model demonstrates that loss of the evolutionarily highly conserved CWF19L1, whose normal biological function is unknown, alters cerebellar morphology and causes movement abnormalities. Conclusions:Our results suggest that CWF19L1 mutations may be a novel cause of recessive ataxia with developmental delay. Our research may help with diagnosis, especially in Turkey, identify causes of other ataxias, and may lead to novel therapies. Neurology ® 2014;83:2175-2182 GLOSSARY CWF19L1 5 complexed with cdc5 protein 19-like 1; GAPDH 5 glyceraldehyde 3-phosphate dehydrogenase; LCL 5 lymphoblastoid cell line; MO 5 morpholino oligonucleotide; mRNA 5 messenger RNA; qRT 5 quantitative reverse transcription.

Pathogenic CWF19L1 variants as a novel cause of autosomal recessive cerebellar ataxia and atrophy

“…3 The authors showed that knockdown of the homolog of CWF19L1 in zebrafish results in cerebellar and movement abnormalities and that the encoded protein C19L1 is expressed throughout the brain suggesting an important role for C19L1 in neural development. 3 Although the exact function of the C19L1 is still unknown, the nuclear localization in combination with a metallophosphatase domain, which is found in RNA lariat debranching enzymes, suggests a role in mRNA processing. 3 However, further studies are needed to determine the exact function of this protein and its role in brain development.…”

“…3 Although the exact function of the C19L1 is still unknown, the nuclear localization in combination with a metallophosphatase domain, which is found in RNA lariat debranching enzymes, suggests a role in mRNA processing. 3 However, further studies are needed to determine the exact function of this protein and its role in brain development. Detailed functional characterization of C19L1 will provide more information on different causes of ARCA and possibly reveal novel candidates for the analysis of pathogenic variants in patients and/or targets for therapy.…”

“…2 Recently, pathogenic variants were described in a novel gene (CWF19L1) in two siblings with autosomal recessive ataxia syndrome. 3 Here, we report a second case, a girl from non-consanguineous Dutch parents, with cerebellar ataxia and atrophy, who was compound heterozygous for pathogenic variants in the CWF19L1 gene. Our results confirm the suggested role of CWF19L1 in rare cases of autosomal recessive cerebellar ataxia.…”

Structure of a yeast spliceosome at 3.6-angstrom resolution

“…These include five NTC core components: Cdc5, which plays an important role in pre-mRNA splicing by stabilizing the second-step spliceosome (60-62); Cwf7, which modulates interactions of Prp19 with other associated cofactors (63,64); Cwf2/Prp3, which helps link NTC to the catalytic center; Cwf1/Prp5, which contains a 7-bladed β-propeller; and Cwf15, which interacts with U5 snRNA, Prp5, and Spp42. In addition, we modeled four NTR components: Cwf5/Ecm2, which is involved in base pairing interactions of U2/U6 helix II (65); Cwf11, which is an ARM domain containing RNA helicase (49); Cwf14, which facilitates both steps of the splicing reaction (66); and Cwf19, Whose human ortholog is thought to be involved in the development of recessive ataxia syndrome (67). We also identified Prp17 and the prolyl isomerase Cyp1 in the EM density map.…”

CANPMR Syndrome and Chromosome 1p32-p31 Deletion Syndrome Coexist in Two Related Individuals Affected by Simultaneous Haplo-insufficiency of CAMTA1 and NIFA Genes

“…The affected patients present with ataxic gait, dysmetries, variable mental retardation, cerebellar abnormalities and dysmorphic facies with heterogeneous penetrance. To date few genes/loci have been associated to autosomal recessive forms of cerebellar ataxias: ATCAY [5], chromosome 20q11-q13 locus [6], VLDLR [7], ZNF592 [8], SPTBN2 [9], CWF19L1 [10], PMPCA [11]. Calmodulinbinding transcription activator 1 (CAMTA1) maps on chromosome 1p36, carries 23 exons and encodes 2 protein isoforms in mammalians.…”