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.
- 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
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Funding This work was supported by the Rappaport Institute for Research Haifa to TCFZ, Israel; Microsoft Inc 2009331 to TCFZ; and the Intramural Research Program of the National Human Genome Research Institute, National Institute of Health, Z99HG999999 to WW.
Competing interests None.
Patient consent All study participants and parents of minors signed locally approved and appropriate informed consent forms, delivered by board certified geneticists/genetic counselors able to communicate in the patients' local language, following local and international Helsinki committees' directives. The anonymity of patients is kept.
Ethics approval The ethics approval was provided by the Ethics committee of Western Galilee Hospital, Nahariya, Israel and by the supreme Ethics committee of the Israeli Ministry of Health.
Provenance and peer review Not commissioned; externally peer reviewed.