Mutation in Clorf131, encoding a novel nucleolar protein, causes intellectual disability in a large Pakistani family
The 52º European Society of Human Genetics (ESHG)conference .
Abstract:
Intellectual disability (ID) is characterized by substantial limitations in both intellectual functioning and adaptive behavior. 50% of ID cases have genetic basis. It can also be categorized as syndromic intellectual disability (S-ID) and non-syndromic intellectual disability (NS-ID). Worldwide prevalence of this disorder is estimated to range from 1% to 3%. Material and Methods: For genomic analyses, homo- zygosity mapping was coupled with whole-exome sequencing (WES) whereas immunofluorescence, confocal microscopy, pulldown assays and mass spectrometry analyses were performed for biochemical analyses. Results: We studied a Pakistani family of NS-ID and identified linkage regions with a maximum possible LOD score of 2.4 at chromosomes 1, 2, 15 and 21. WES con- ducted on DNA of two affected members revealed a missense mutation (NM_152379.3:c.112G>A,p. Asp38Asn) in Clorf13l, encoding the uncharacterized protein Clorf131, as a likely cause of ID. The mutation replaces a highly conserved aspartic acid by asparagine and is predicted to be pathogenic by Mutation Taster and Polyphen-2. We show here that Clorfl31 is a novel nucleolar component and relocates to the chromosomal periphery during mitosis. Mutant primary fibroblasts exhibit reduced and distorted nucleoli, micronuclei and misshapen nuclei. Similar effects are seen upon overexpression of mutant protein or knock- down by siRNA. Our data also show that Clorf131 interacts with several nucleolar and centrosomal proteins. Conclusion: We conclude that Clorf131 is a novel gene associated with ID and that its protein product plays a crucial role in maintaining the structural integrity of the nucleolus. It is also an essential component for normal brain function.
