RT Journal Article
SR Electronic
T1 A founder mutation in Vps37A causes autosomal recessive complex hereditary spastic paraparesis
JF Journal of Medical Genetics
JO J Med Genet
FD BMJ Publishing Group Ltd
SP 462
OP 472
DO 10.1136/jmedgenet-2012-100742
VO 49
IS 7
A1 Zivony-Elboum, Yifat
A1 Westbroek, Wendy
A1 Kfir, Nehama
A1 Savitzki, David
A1 Shoval, Yishay
A1 Bloom, Assnat
A1 Rod, Raya
A1 Khayat, Morad
A1 Gross, Bella
A1 Samri, Walid
A1 Cohen, Hector
A1 Sonkin, Vadim
A1 Freidman, Tatiana
A1 Geiger, Dan
A1 Fattal-Valevski, Aviva
A1 Anikster, Yair
A1 Waters, Aoife M
A1 Kleta, Robert
A1 Falik-Zaccai, Tzipora C
YR 2012
UL http://jmg.bmj.com/content/49/7/462.abstract
AB 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.