Familial Deafness, Congenital Heart Defects, and Posterior Embryotoxon Caused by Cysteine Substitution in the First Epidermal-Growth-Factor–Like Domain.

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Familial Deafness, Congenital Heart Defects, and Posterior Embryotoxon Caused by Cysteine Substitution in the First Epidermal-Growth-Factor–Like Domain of Jagged 1 C. Le Caignec, M. Lefevre, J.J. Schott, A. Chaventre, M. Gayet, C. Calais, J.P. Moisan The American Journal of Human Genetics Volume 71, Issue 1, Pages 180-186 (July 2002) DOI: 10.1086/341327 Copyright © 2002 The American Society of Human Genetics Terms and Conditions

Figure 1 Pedigree of the family with deafness and congenital heart defects, showing three-locus genotypes and inferred haplotypes. Unblackened symbols denote unaffected individuals; blackened symbols denote affected individuals. Genotypes are shown in the following order, from top to bottom: D20S115, D20S186, and D20S112. The arrow indicates the proband. The American Journal of Human Genetics 2002 71, 180-186DOI: (10.1086/341327) Copyright © 2002 The American Society of Human Genetics Terms and Conditions

Figure 2 A, Axial CT scan of patient III-6, showing aplasia of the anterior semicircular canal (a) and hypoplasia of the posterior semicircular canal (p). B, Comparison with an unaffected individual. The American Journal of Human Genetics 2002 71, 180-186DOI: (10.1086/341327) Copyright © 2002 The American Society of Human Genetics Terms and Conditions

Figure 3 Representative audiogram for the family (individual II-7) The American Journal of Human Genetics 2002 71, 180-186DOI: (10.1086/341327) Copyright © 2002 The American Society of Human Genetics Terms and Conditions

Figure 4 Sequence chromatograms showing the mutation found in the kindred. A, Sequencing data from individual II-8, representing the normal JAG1 allele. B, Sequencing data from an affected patient (II-7), representing the normal and the mutant JAG1 alleles. A G→A transition changes the codon for cysteine (TGC) in position 234 of the JAG1 protein to the codon for tyrosine (TAC). The American Journal of Human Genetics 2002 71, 180-186DOI: (10.1086/341327) Copyright © 2002 The American Society of Human Genetics Terms and Conditions

Figure 5 A, Schematic diagram of human JAG1, mouse Jag1, and Drosophila Delta and Serrate protein structures, and the locations of missense mutations identified in EGF-like domains of human JAG1 and in the second EGF-like domain of mouse Jag1. The arrows indicate C-terminal deletions of Delta and Serrate. Superscripts associated with mutations are as follows: a = missense mutation described in the present study; b = mutation described in a kindred segregating ToF and characteristic facies; c = mutations described in patients with AGS; d = mutation described in mouse Slalom mutant; e = mutation described in mouse Headturner mutant. SP = signal peptide; DSL = conserved domain shared by Delta, Serrate, and Lag2; CR = cysteine-rich region; TM = transmembrane domain; IC = intracellular domain. B, Alignment of the amino acid sequence of the first EGF-like domain of human JAG1 with the corresponding sequences of the first EGF-like domain of human JAG2, the second EGF-like domain of human JAG1, and those from other species. Note the first cysteine is conserved in all of the wild-type sequences. The American Journal of Human Genetics 2002 71, 180-186DOI: (10.1086/341327) Copyright © 2002 The American Society of Human Genetics Terms and Conditions