PT  - JOURNAL ARTICLE
AU  - Zivony-Elboum, Yifat
AU  - Westbroek, Wendy
AU  - Kfir, Nehama
AU  - Savitzki, David
AU  - Shoval, Yishay
AU  - Bloom, Assnat
AU  - Rod, Raya
AU  - Khayat, Morad
AU  - Gross, Bella
AU  - Samri, Walid
AU  - Cohen, Hector
AU  - Sonkin, Vadim
AU  - Freidman, Tatiana
AU  - Geiger, Dan
AU  - Fattal-Valevski, Aviva
AU  - Anikster, Yair
AU  - Waters, Aoife M
AU  - Kleta, Robert
AU  - Falik-Zaccai, Tzipora C
TI  - A founder mutation in Vps37A causes autosomal recessive complex hereditary spastic paraparesis
AID  - 10.1136/jmedgenet-2012-100742
DP  - 2012 Jul 01
TA  - Journal of Medical Genetics
PG  - 462--472
VI  - 49
IP  - 7
4099  - http://jmg.bmj.com/content/49/7/462.short
4100  - http://jmg.bmj.com/content/49/7/462.full
SO  - J Med Genet2012 Jul 01; 49
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.