title: Hypomyelination and developmental delay associated with VPS11 mutation in Ashkenazi-Jewish patients.
abstract: BACKGROUND
  The genetic heterogeneity of developmental delay and cognitive impairment is vast. The endocytic network is essential for neural development and synaptic plasticity by regulating the sorting of numerous transmembrane proteins. Disruption of the pathway can lead to neuronal pathology. Endosomal biogenesis relies on two Rab proteins, Rab5 and Rab7, which bind to two hexameric tethering complexes, the endosomal class C core vacuole/endosome tethering complex (CORVET) and the late endosomal/lysosomal homotypic fusion and protein sorting complex (HOPS). Both complexes consist of four core proteins and differ by their specific Rab-binding proteins.
  
  
  OBJECTIVE
  To identify the molecular basis of a neurological disease, which consists of global developmental stagnation at 3-8 months, increasing appendicular spasticity, truncal hypotonia and acquired microcephaly, with variable seizure disorder, accompanied by thin corpus callosum, paucity of white matter and delayed myelination in eight patients from four unrelated Ashkenazi-Jewish (AJ) families.
  
  
  METHODS
  Exome analysis, homozygosity mapping and Mup1-GFP transport assay in mutant yeast.
  
  
  RESULTS
  Homozygosity for a missense mutation, p.Cys846Gly, in one of the endosomal biogenesis core proteins, VPS11, was identified in all the patients. This was shown to be a founder mutation with a carrier frequency of 0.6% in the AJ population. The homologous yeast mutant had moderate impairment of fusion of the late endosome to the vacuole in Mup1-GFP transport assay.
  
  
  CONCLUSIONS
  We speculate that in neuronal cells, impairment of fusion of the late endosome to the vacuole would attenuate the degradation of plasma membrane receptors, thereby underlying the progressive neuronal phenotype in our patients. The VPS11 p.Cys846Gly mutation should be added to the AJ carrier screening panel.
authors: Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors: Shimon
authors: S
authors: Edvardson
authors: Department of Biology/Chemistry, Biochemistry Section, University of Osnabrück, Osnabrück, Germany.
authors: Frank
authors: F
authors: Gerhard
authors: Bonei Olam, Center for Rare Jewish Genetic Disorders, Brooklyn, New York, USA.
authors: Chaim
authors: C
authors: Jalas
authors: Department of Biology/Chemistry, Biochemistry Section, University of Osnabrück, Osnabrück, Germany.
authors: Jens
authors: J
authors: Lachmann
authors: Maccabi Health Services, Child Development Center, Jerusalem, Israel.
authors: Dafna
authors: D
authors: Golan
authors: Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors: Ann
authors: A
authors: Saada
authors: Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors: Avraham
authors: A
authors: Shaag
authors: Department of Biology/Chemistry, Biochemistry Section, University of Osnabrück, Osnabrück, Germany.
authors: Christian
authors: C
authors: Ungermann
authors: Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors: Orly
authors: O
authors: Elpeleg
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000378:metabolism; D000293:Adolescent; D002648:Child; D004252:DNA Mutational Analysis; D002658:Developmental Disabilities / Q000235:genetics* / Q000378:metabolism; D011992:Endosomes / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D007223:Infant; D007585:Jews / Q000235:genetics; D008297:Male; D008831:Microcephaly / Q000235:genetics / Q000378:metabolism; D009123:Muscle Hypotonia / Q000235:genetics / Q000378:metabolism; D020125:Mutation, Missense; D009186:Myelin Sheath / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010375:Pedigree; D012441:Saccharomyces cerevisiae; D013577:Syndrome; D033921:Vesicular Transport Proteins / Q000235:genetics*; D055815:Young Adult
chemical_list: C424438:VPS11 protein, human; D033921:Vesicular Transport Proteins
keywords: Neurology