A founder mutation in Vps37A causes autosomal recessive complex hereditary spastic paraparesis. Issue 7 (20th June 2012)

• Record Type: Journal Article
• Authors: Zivony-Elboum, Yifat; Westbroek, Wendy; Kfir, Nehama; Savitzki, David; Shoval, Yishay; Bloom, Assnat; Rod, Raya; Khayat, Morad; Gross, Bella; Samri, Walid; Cohen, Hector; Sonkin, Vadim; Freidman, Tatiana; Geiger, Dan; Fattal-Valevski, Aviva; Anikster, Yair; Waters, Aoife M; Kleta, Robert; Falik-Zaccai, Tzipora C
• Is Part Of: Journal of medical genetics. Volume 49:Issue 7(2012)
• Page Start: 462
• Page End: 472
• Publication Date: 2012-06-20
• Subjects: Endosomal sorting complex required for transport system -- linkage analysis -- haplotype reconstruction -- morpholino oligonucleotide injected zebrafish -- rare disease -- renal medicine -- molecular genetics -- clinical genetics -- genetic screening/counselling -- cytogenetics -- genetics; Medical genetics -- Periodicals; 616.042
• DOI: 10.1136/jmedgenet-2012-100742
• Languages: English
• ISSNs: 1468-6244

Abstract

Abstract : Background: Members of two seemingly unrelated kindreds of Arab Moslem origin presented with pronounced early onset spastic paraparesis of upper and lower limbs, mild intellectual disability, kyphosis, pectus carinatum and hypertrichosis. Methods: The authors performed neurological and developmental examinations on the affected individuals. The authors conducted whole genome linkage and haplotype analyses, followed by sequencing of candidate genes; RNA and protein expression studies; and finally proof of principle investigations on knockdown morpholino oligonucleotide injected zebrafish. Results: The authors characterise a novel form of autosomal recessive complex hereditary spastic paraparesis (CHSP). MRI studies of brain and spinal cord were normal. Within a single significantly linked locus the authors ultimately identified a homozygous missense mutation c.1146A>T (p.K382N) in the vacuolar protein sorting 37A ( Vps37A ) gene, fully penetrant and segregating with the disease in both families. Mobility was significantly reduced in Vps37A knockdown morpholino oligonucleotide injected zebrafish, supporting the causal relationship between mutations in this gene and the phenotype described in the patients of this study. Conclusions: The authors provide evidence for the involvement of Vps37A, a member of the endosomal sorting complex required for transport (ESCRT) system, in upper motor neuron disease. The ESCRT system has been shown to play a central role in intracellular trafficking, in the maturation of multivesicular bodies and the sorting of ubiquitinated membrane proteins into internal luminal vesicles. Further investigation of mechanisms by which dysfunction of this gene causes CHSP will contribute to the understanding of intracellular trafficking of vesicles by the ESCRT machinery and its relevance to CHSP.