Autosomal recessive infantile bilateral striatal necrosis is caused by a mutation in the nup62 gene
Purpose: The purpose of this study was to identify the gene causing autosomal recessive Infantile Bilateral Striatal Necrosis (IBSN). IBSN is characterized clinically by developmental arrest beginning at the age of 1 year, dysphagia, choreoathetosis, pendular nystagmus, optic atrophy and severe progressive atrophy of the basal ganglia on MRI.
Methods: By homozygosity mapping and linkage analysis, we have mapped the disease gene to the candidate region of ~230 kb on 19q13.33 between the markers rs8101959 and D19S867 in eight interrelated families including in total 12 patients and 39 unaffected individuals. We have sequenced exons and exon-intron boundaries of all 13 genes in the candidate region.
Results: Sequencing of the nup62 gene revealed a missense mutation causing a change from glutamine to proline (Q391P) in exon 3 in all the patients. No pathogenic sequence changes were found in all the other genes. The mutation was not found in 400 control chromosomes from ethnically unrelated individuals. It was found only in the heterozygous state in 12 out of 280 control chromosomes originating in the Bedouin controls living in the same geographic area as the original families, as expected because of the high frequency of carriers within this population. Comparisons of p62 protein sequences from diverse species indicate that glutamine at position 391 is highly conserved. The Q391P mutation produces a substitution that results in a change from a polar, hydrophilic residue to a non-polar, neutral residue. Five prenatal diagnoses were performed in three at-risk families.
Conclusions: This is the second example of a nuclear pore complex protein causing mendelian disease in humans (the first is tripple A syndrome). Our findings suggest that nup62 has a cell type-specific role and is important in the degeneration of the basal ganglia.