A Novel Point Mutation Affecting the Tyrosine Kinase Domain of the TRKA Gene in a Family with Congenital Insensitivity to Pain with Anhidrosis Shinichi.

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A Novel Point Mutation Affecting the Tyrosine Kinase Domain of the TRKA Gene in a Family with Congenital Insensitivity to Pain with Anhidrosis Shinichi Yotsumoto, Mitsuru Setoyama, Hideki Hozumi, Shimako Mizoguchi, Seita Fukumaru, Tamotsu Kanzaki Journal of Investigative Dermatology Volume 112, Issue 5, Pages 810-814 (May 1999) DOI: 10.1046/j.1523-1747.1999.00569.x Copyright © 1999 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 1 Pedigree and genotype of Met-581-Val mutation and del C1726 mutation in the TRKA gene of the CIPA family over five generations. Proband (IV-5) is indicated by an arrow. Asterisks represent affected patients. Half-black circles and squares represent heterozygous carriers, black circles represent homozygous patients with the Met-581-Val mutation in the TRKA gene. Half-hatched square represents heterozygous carriers, half-hatched and black circle represents a compound heterozygote of the del C1726 and Met-581-Val mutations in the TRKA gene. Figures with diagonal lines represent deceased individuals. The ages of the family members tested are shown. Journal of Investigative Dermatology 1999 112, 810-814DOI: (10.1046/j.1523-1747.1999.00569.x) Copyright © 1999 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 2 Clinical appearance and X-ray finding of patients with CIPA. The proband (IV-5) (a, b) and the patient (V-3) (c) show that the joint destruction caused by the failure to react to painful stimuli was the most prominent feature. Journal of Investigative Dermatology 1999 112, 810-814DOI: (10.1046/j.1523-1747.1999.00569.x) Copyright © 1999 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 3 The proband and the patient V-3 were homozygous for the Met-581-Val mutation. (a) Sequence analysis of exon 14 and the flanking intronic sequence of the TRKA gene from genomic DNA reveals a homozygous A-to-G transition (asterisks) at position 1825 in the mutant allele (lower panel) as compared with the normal control sequence (upper panel). The mutation changes codon ATG to GTG (Met-581-Val). (b) Scheme of the fragment pattern of the PCR products formed by restriction enzyme NlaIII digestion. The nucleotide substitution abolishes a NlaIII restriction enzyme site. In a normal allele, the 377 bp PCR product is digested to 226, 88, and 63 bp fragments, whereas in a mutant allele, 289 and 88 bp fragments appear. (c) Restriction enzyme digestion analysis of the genomic region around the mutation in family members III-11, III-12, IV-9, IV-10, and V-3 as shown in Figure 1. The 377 bp PCR products were digested with NlaIII and electrophoresed on a 3% agarose gel. Analysis of the PCR product for each individual is shown below the corresponding symbols in the pedigree. M, molecular marker; U, undigested PCR product; C, normal control individual. Journal of Investigative Dermatology 1999 112, 810-814DOI: (10.1046/j.1523-1747.1999.00569.x) Copyright © 1999 The Society for Investigative Dermatology, Inc Terms and Conditions

Figure 4 The third patient V-1 is a compound heterozygote for the Met-581-Val mutation and the del C1726 mutation in exon 14. (a) Sequence analysis of exon 14 and the flanking intronic sequence of the TRKA gene from genomic DNA reveals a deletion of a single base C at nucleotide 1726 (asterisks) in the mutant allele (lower panel) as compared with the normal control sequence (upper panel), causing a frameshift and premature termination codon downstream. (b) Scheme of the fragment pattern of the PCR products formed by digestion with restriction enzyme Bsp1286I. The nucleotide deletion abolishes a Bsp1286I restriction enzyme site. In a normal allele, the 377 bp PCR product is digested to 194, 96, 48, and 39 bp fragments, whereas in the mutant allele, 241, 96, and 39 bp fragments appear after Bsp1286I digestion. (c) Restriction enzyme digestion analysis of the genomic region around the mutation in family members IV-3, IV-4, and V-1 as shown in Figure 1. PCR products of 377 and 366 bp were digested with NlaIII (upper panel), and with Bsp1286I (lower panel), and electrophoresed on a 3% agarose gel, respectively. Analysis of the PCR product for each individual is shown below the corresponding symbols in the pedigree. Solid halves represent the maternally inherited Met-581-Val mutation; striped halves represent the paternally inherited del C1726 mutation. M, molecular marker. Journal of Investigative Dermatology 1999 112, 810-814DOI: (10.1046/j.1523-1747.1999.00569.x) Copyright © 1999 The Society for Investigative Dermatology, Inc Terms and Conditions