A Unique Point Mutation in the PMP22 Gene Is Associated with Charcot-Marie-Tooth Disease and Deafness Margaret J. Kovach, Jing-Ping Lin, Simeon Boyadjiev,

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A Unique Point Mutation in the PMP22 Gene Is Associated with Charcot-Marie-Tooth Disease and Deafness Margaret J. Kovach, Jing-Ping Lin, Simeon Boyadjiev, Kathleen Campbell, Larry Mazzeo, Kristin Herman, Lisa A. Rimer, William Frank, Barbara Llewellyn, Ethylin Wang Jabs, David Gelber, Virginia E. Kimonis The American Journal of Human Genetics Volume 64, Issue 6, Pages 1580-1593 (June 1999) DOI: 10.1086/302420 Copyright © 1999 The American Society of Human Genetics Terms and Conditions

Figure 1 Pedigree of family affected with autosomal dominant CMT and deafness showing haplotype analysis for 15 markers on 17p11.2. Markers are listed top to bottom: telomere-D1S921-D17S839-D17S1357-CMT-D17S122-D17S261-D17S1857-D17S953-D17S1843-D17S740-D17S71-D17S2207-D17S2201-D17S842-D17S959-D17S783-centromere. For each marker, the alleles were numbered on the basis of sizes reported in the Genome Database. Novel alleles were assigned numbers after the last reported allele in the Genome Database. The site of the CMT1A/PMP22 gene locus is included in relation to its position to the molecular markers. A plus sign (+) designates the disease allele; a minus sign (−), the nondisease allele. The boldfaced bars represent the disease haplotype linked to CMT with deafness. Circles denote females, squares denote males, slashed symbol denotes deceased individuals, blackened symbol denotes affected individuals. An arrow indicates the proband. The American Journal of Human Genetics 1999 64, 1580-1593DOI: (10.1086/302420) Copyright © 1999 The American Society of Human Genetics Terms and Conditions

Figure 1 Pedigree of family affected with autosomal dominant CMT and deafness showing haplotype analysis for 15 markers on 17p11.2. Markers are listed top to bottom: telomere-D1S921-D17S839-D17S1357-CMT-D17S122-D17S261-D17S1857-D17S953-D17S1843-D17S740-D17S71-D17S2207-D17S2201-D17S842-D17S959-D17S783-centromere. For each marker, the alleles were numbered on the basis of sizes reported in the Genome Database. Novel alleles were assigned numbers after the last reported allele in the Genome Database. The site of the CMT1A/PMP22 gene locus is included in relation to its position to the molecular markers. A plus sign (+) designates the disease allele; a minus sign (−), the nondisease allele. The boldfaced bars represent the disease haplotype linked to CMT with deafness. Circles denote females, squares denote males, slashed symbol denotes deceased individuals, blackened symbol denotes affected individuals. An arrow indicates the proband. The American Journal of Human Genetics 1999 64, 1580-1593DOI: (10.1086/302420) Copyright © 1999 The American Society of Human Genetics Terms and Conditions

Figure 2 Genetic map of chromosome 17p11.2 markers. The sites for the autosomal recessive deafness (DFNB3) locus and CMT type 1A duplication region are indicated. The CMT and deafness critical region, defined by markers D17S839 and D17S122, is represented by a boldfaced bar. Genetic distances and placement of PMP22 were obtained from PAC/BAC map of the CMT type 1A duplication region (personal communication, Dr. J. R. Lupski). The American Journal of Human Genetics 1999 64, 1580-1593DOI: (10.1086/302420) Copyright © 1999 The American Society of Human Genetics Terms and Conditions

Figure 3 A, Identification of the G→C mutation in PMP22 exon 4. The sense and antisense sequences are shown for an unaffected (V:7) and an affected (VI:19) family member. An arrow indicates the location of the G→C heterozygous point mutation. Note that the automatic sequence generated miscalled the mutated nucleotide in the sense strand, but the peak height has changed in the affected individual. B, Confirmation of G→C heterozygous point mutation by RFLP analysis. This point mutation results in the loss of a restriction cut site for enzyme HaeIII. Digestion of genomic DNA from the unaffected individual (V:7) produced two fragments of 159 and 55 bp. RFLP analysis of the affected individual (VI:19) generated three fragments of 214, 159, and 55 bp, representing the heterozygous state of mutation. The 55-bp restriction fragment is not shown in this gel. The American Journal of Human Genetics 1999 64, 1580-1593DOI: (10.1086/302420) Copyright © 1999 The American Society of Human Genetics Terms and Conditions

Figure 4 Proposed protein structure of PMP22 (figure adopted from Roa et al. 1993a). PMP22 is predicted to have four transmembrane domains (TM1–TM4) and one N-glycosylation site (N41) (Suter et al. 1992a). A β-sheet conformation is predicted for domains TM1, 2, and 4, whereas TM3 is thought to be α-helical in nature. The 160 amino acids of PMP22 are represented in single-letter code. Substitutions because of single-base point mutations are shaded, with an arrow pointing to the designation of the changed residue. The unique substitution associated with CMT and deafness (Ala67Pro) reported in this paper is represented by an asterisk (∗). Point mutations observed in patients given a clinical diagnosis of CMT are double encircled. Circles wrapped by a square designate the two mutations in which deafness was reported elsewhere, in addition to CMT. Mutations identical to the trembler (Gly150Asp) and trembler-J (Leu16Pro) mouse genotypes are indicated by a diamond (⋄). Multiple substitutions have been reported for three residues (Ser72, Ser79, and Gly100). The American Journal of Human Genetics 1999 64, 1580-1593DOI: (10.1086/302420) Copyright © 1999 The American Society of Human Genetics Terms and Conditions