Lethal Contractural Syndrome Type 3 (LCCS3) Is Caused by a Mutation in PIP5K1C, Which Encodes PIPKIγ of the Phophatidylinsitol Pathway Ginat Narkis,

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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 The American Journal of Human Genetics Volume 81, Issue 3, Pages 530-539 (September 2007) DOI: 10.1086/520771 Copyright © 2007 The American Society of Human Genetics Terms and Conditions

Figure 1 Israeli-Bedouin kindreds affected with LCCS3. Blackened and unblackened symbols represent affected and unaffected individuals, respectively. Numbers denote individuals whose DNA samples were analyzed. A, Pedigree of family A. B, Pedigree of family B. The American Journal of Human Genetics 2007 81, 530-539DOI: (10.1086/520771) Copyright © 2007 The American Society of Human Genetics Terms and Conditions

Figure 2 LCCS3-affected fetus at 16 wk gestation The American Journal of Human Genetics 2007 81, 530-539DOI: (10.1086/520771) Copyright © 2007 The American Society of Human Genetics Terms and Conditions

Figure 3 Linkage results for chromosome 19 for a partial pedigree of family A. The haplotype showing the homozygosity region is boxed. Arrows indicate crossing-over events. The upper and lower boundaries were determined according to individuals 14 and 8, respectively. The American Journal of Human Genetics 2007 81, 530-539DOI: (10.1086/520771) Copyright © 2007 The American Society of Human Genetics Terms and Conditions

Figure 4 The G757A mutation in exon 7 of PIP5K1C. A, Sequence analysis of the A→G substitution in an unaffected individual, obligate carrier, and affected individual. chr = Chromosome. B, PIP5K1C exon 7 mutation scanned with TaqI restriction enzyme, with schematic diagram illustrating the Taq1 fragments. C, Mutation analysis of family A members. PCR amplification products were digested with Taq1 restriction enzyme and were separated on 2% agarose gel. C = unrelated healthy control. Individuals 7, 8, 11, and 14 were homozygous for the mutated allele. Individuals 1, 3, 4, 6, 12, and 13 were heterozygous for the wild-type and mutated alleles. Individuals 2 and 5 were homozygous for the wild-type allele. The American Journal of Human Genetics 2007 81, 530-539DOI: (10.1086/520771) Copyright © 2007 The American Society of Human Genetics Terms and Conditions

Figure 5 The D253N PIP5K1C mutation in LCCS3, which abolishes the PIP5K1C kinase activity. A, Prediction of the structural and functional importance of the aspartic acid residue at position 253, done using the ConSeq server. The ConSeq conservation grade was 9 (highly conserved). B, The aspartic acid at position 253, which is within a conserved DLKGS motif in the PIPK domain of the PIP5K1C protein. C, Purified wild-type (WT) and mutant (M) recombinant GST-PIP5K1C fusion proteins (SDS-PAGE). D, Kinase activity of wild-type (WT) and mutant (M) PIP5K1C recombinant proteins, tested in a reaction mixture containing PI4P (80 μM) as substrate and [γ32P]ATP. The labeled PIP2 product was separated using thin-layer chromatography and was quantified by phosphor-imaging analysis. PIP2 (mean±SD of three independent experiments) synthesized by mutant recombinant PIP5K1C was 1.7%±0.56% of PIP2 synthesized by equal amount of wild-type PIP5K1C. GST = glutathione S-transferase (negative control). The American Journal of Human Genetics 2007 81, 530-539DOI: (10.1086/520771) Copyright © 2007 The American Society of Human Genetics Terms and Conditions