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.
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.
Authors: Paulo Victor Sgobbi de Souza; Wladimir Bocca Vieira de Rezende Pinto; Gabriel Novaes de Rezende Batistella; Thiago Bortholin; Acary Souza Bulle Oliveira Journal: Cerebellum Date: 2017-04 Impact factor: 3.847
Authors: Tzipora C Falik Zaccai; David Savitzki; Yifat Zivony-Elboum; Thierry Vilboux; Eric C Fitts; Yishay Shoval; Limor Kalfon; Nadra Samra; Zohar Keren; Bella Gross; Natalia Chasnyk; Rachel Straussberg; James C Mullikin; Jamie K Teer; Dan Geiger; Daniel Kornitzer; Ora Bitterman-Deutsch; Abraham O Samson; Maki Wakamiya; Johnny W Peterson; Michelle L Kirtley; Iryna V Pinchuk; Wallace B Baze; William A Gahl; Robert Kleta; Yair Anikster; Ashok K Chopra Journal: Brain Date: 2016-12-21 Impact factor: 13.501
Authors: Gaia Novarino; Ali G Fenstermaker; Maha S Zaki; Matan Hofree; Jennifer L Silhavy; Andrew D Heiberg; Mostafa Abdellateef; Basak Rosti; Eric Scott; Lobna Mansour; Amira Masri; Hulya Kayserili; Jumana Y Al-Aama; Ghada M H Abdel-Salam; Ariana Karminejad; Majdi Kara; Bulent Kara; Bita Bozorgmehri; Tawfeg Ben-Omran; Faezeh Mojahedi; Iman Gamal El Din Mahmoud; Naima Bouslam; Ahmed Bouhouche; Ali Benomar; Sylvain Hanein; Laure Raymond; Sylvie Forlani; Massimo Mascaro; Laila Selim; Nabil Shehata; Nasir Al-Allawi; P S Bindu; Matloob Azam; Murat Gunel; Ahmet Caglayan; Kaya Bilguvar; Aslihan Tolun; Mahmoud Y Issa; Jana Schroth; Emily G Spencer; Rasim O Rosti; Naiara Akizu; Keith K Vaux; Anide Johansen; Alice A Koh; Hisham Megahed; Alexandra Durr; Alexis Brice; Giovanni Stevanin; Stacy B Gabriel; Trey Ideker; Joseph G Gleeson Journal: Science Date: 2014-01-31 Impact factor: 47.728