Lethal contractural syndrome type 3 (LCCS3) is caused by a mutation in PIP5K1C, which encodes PIPKIγ of the phophatidylinsitol pathway

Ginat Narkis, Rivka Ofir, Daniella Landau, Esther Manor, Micha Volokita, Relly Hershkowitz, Khalil Elbedour, Ohad S. Birk

Research output: Contribution to journalArticlepeer-review

67 Scopus citations

Abstract

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 PIPSK1C. PIPSK1C encodes phosphatidylinositol-4-phosphate 5-kinase, type I, gamma (PIPKIγ), an enzyme that phophorylates phosphatidylinositol 4-phosphate to generate phosphatidylinositol-4,5-bisphosphate (PIP2). We demonstrate that the mutation causes substitution of aspartic acid with asparagine at amino acid 253 (D253N), abrogating the kinase activity of PIPKIγ. 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.

Original languageEnglish
Pages (from-to)530-539
Number of pages10
JournalAmerican Journal of Human Genetics
Volume81
Issue number3
DOIs
StatePublished - 1 Jan 2007

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