Lethal contractural syndrome type 3 (LCCS3) is caused by a mutation in PIP5K1C, which encodes PIPKI gamma of the phophatidylinsitol pathway.
Lethal congenital contractural syndrome (LCCS) is a severe form of arthrogryposis. To date, two autosomal recessive forms of the disease (LCCS and LCCS2) have been described and mapped to chromosomes 9q34 and 12q13, respectively. We now describe a third LCCS phenotype (LCCS3)--similar to LCCS2 yet without neurogenic bladder. Using 10K single-nucleotide-polymorphism arrays, we mapped the disease-associated gene to 8.8 Mb on chromosome 19p13. Further analysis using microsatallite markers narrowed the locus to a 3.4-Mb region harboring 120 genes. Of these genes, 30 candidates were sequenced, which identified a single homozygous mutation in PIP5K1C. PIP5K1C encodes phosphatidylinositol-4-phosphate 5-kinase, type I, gamma (PIPKI gamma ), an enzyme that phophorylates phosphatidylinositol 4-phosphate to generate phosphatidylinositol-4,5-bisphosphate (PIP(2)). We demonstrate that the mutation causes substitution of aspartic acid with asparagine at amino acid 253 (D253N), abrogating the kinase activity of PIPKI gamma . Thus, a defect in the phosphatidylinositol pathway leading to a decrease in synthesis of PIP(2), a molecule active in endocytosis of synaptic vesicle proteins, culminates in lethal congenital arthrogryposis.
Narkis
Ginat
G
Morris Kahn Laboratory of Human Genetics, National Institute of Biotechnology in Negev, Beer-Sheva, Israel.
Ofir
Rivka
R
Landau
Daniella
D
Manor
Esther
E
Volokita
Micha
M
Hershkowitz
Relly
R
Elbedour
Khalil
K
Birk
Ohad S
OS
D000483:Alleles; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001176:Arthrogryposis / Q000235:genetics*; D001216:Asparagine / Q000737:chemistry / Q000235:genetics; D001224:Aspartic Acid / Q000737:chemistry / Q000235:genetics; D002888:Chromosomes, Human, Pair 19 / Q000235:genetics; D005260:Female; D006720:Homozygote; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000172:deficiency*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D013577:Syndrome
D019269:Phosphatidylinositol 4,5-Diphosphate; D001224:Aspartic Acid; D001216:Asparagine; D017853:Phosphotransferases (Alcohol Group Acceptor); C020077:1-phosphatidylinositol-4-phosphate 5-kinase
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