A founder mutation in Vps37A causes autosomal recessive complex hereditary spastic paraparesis.
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.
Institute of Human Genetics, Western Galilee Hospital-Naharia, Israel.
Yifat
Y
Zivony-Elboum
Wendy
W
Westbroek
Nehama
N
Kfir
David
D
Savitzki
Yishay
Y
Shoval
Assnat
A
Bloom
Raya
R
Rod
Morad
M
Khayat
Bella
B
Gross
Walid
W
Samri
Hector
H
Cohen
Vadim
V
Sonkin
Tatiana
T
Freidman
Dan
D
Geiger
Aviva
A
Fattal-Valevski
Yair
Y
Anikster
Aoife M
AM
Waters
Robert
R
Kleta
Tzipora C
TC
Falik-Zaccai
D000818:Animals; D001921:Brain / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D002874:Chromosome Mapping; D002898:Chromosomes, Human, Pair 8 / Q000235:genetics / Q000378:metabolism; D056827:Endosomal Sorting Complexes Required for Transport / Q000235:genetics* / Q000378:metabolism; D005260:Female; D018703:Founder Effect; D055785:Gene Knockdown Techniques; D005808:Genes, Recessive; D008040:Genetic Linkage; D006239:Haplotypes; D006720:Homozygote; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D012641:Selection, Genetic; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics* / Q000503:physiopathology; D015027:Zebrafish
D056827:Endosomal Sorting Complexes Required for Transport; C496437:VPS37A protein, human