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Genetics of Charcot-Marie-Tooth Disease Type 4A: Mutations

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Genetics of Charcot-Marie-Tooth Disease Type 4A: Mutations 358 LETTER TO JMG J Med Genet: first published as 10.1136/jmg.2004.022178 on 1 April 2005. Downloaded from Genetics of Charcot-Marie-Tooth disease type 4A: mutations, inheritance, phenotypic variability, and founder effect R Claramunt, L Pedrola, T Sevilla, A Lo´pez de Munain, J Berciano, A Cuesta, B Sa´nchez-Navarro, J M Milla´n, G M Saifi, J R Lupski, J J Vı´lchez, C Espino´s, F Palau ............................................................................................................................... J Med Genet 2005;42:358–365. doi: 10.1136/jmg.2004.022178 harcot-Marie-Tooth (CMT) disease is a motor and sensory neuropathy with clinical and genetic hetero- Key points Cgeneity. Patients usually present in the first or second decade of life with distal muscle atrophy in the legs, areflexia, N We investigated the genetics and inheritance of the foot deformity (mainly pes cavus), and steppage gait. In most GDAP1 gene and phenotype expression in a series of cases, hands are also involved as the disease progresses. CMT 106 isolated and 19 familial cases with Charcot- is the most frequent inherited neuropathy, with a prevalence Marie-Tooth disease and Spanish ancestry, for whom in Spain of 28 in 100 000.1 Based on electrophysiological mutations in the PMP22, MPZ, and GJB1 genes had studies and histopathologic findings in nerve biopsies, CMT previously been excluded. has been subcategorised into two main and distinct N We also investigated the existence of founder effects neuropathies: (i) demyelinating CMT (CMT1, MIM 118200) for some recurrent mutations and the origin of these associated with reduction in a nerve conduction velocities (NCVs) in all nerves and segmental demyelination and mutations in patients from different countries. remyelination (‘‘onion bulbs’’); and (ii) axonal CMT (CMT2, N We found mutations in seven isolated patients, three MIM 118220) associated with normal or almost normal autosomal recessive families, and two autosomal NCVs and loss of myelinated axons. Other phenotypes are dominant families. Six out of seven isolated patients associated with motor and sensory nerve involvement: were homozygotes or compound heterozygotes with De´je´rine-Sottas neuropathy (DSN, MIM 145900) is a severe autosomal recessive inheritance and one patient demyelinating neuropathy with onset in infancy, delayed carried a de novo dominant mutation. The mutation motor milestones, and NCVs less than 10 m/s; congenital detection rate in the sporadic patients was 5.6%. hypomyelinating neuropathy (CHN, MIM 605253) is a Patients with homozygous or compound heterozygous http://jmg.bmj.com/ dysmyelinating neuropathy characterised by infantile hypo- genotypes showed a severe disease, whereas hetero- tonia, distal muscle weakness, and marked reduction of zygous patients from the two autosomal dominant NCVs; hereditary neuropathy with liability to pressure palsies families that segregated the R120W mutation showed (HNPP, MIM 162500) is a milder sensory and motor a milder phenotype. neuropathy with periodic episodes of numbness, muscular N We also report a de novo mutation, T157P, which has weakness, and atrophy.2 not been previously described. Haplotype analysis of Genetic heterogeneity is characteristic of the disease not the CMT4A locus confirmed a unique origin for the just because of the large number of genes and loci associated on September 26, 2021 by guest. Protected copyright. with CMT (currently 21 genes),3–5 but also because the Q163X mutation in 13 Spanish chromosomes and six disease may segregate with different Mendelian patterns. The American Hispanic chromosomes. A common origin most frequent pattern of inheritance is autosomal dominant, for two Spanish chromosomes and two Moroccan but autosomal recessive and X linked segregation are also chromosomes carrying the S194X was also confirmed. observed. N We concluded that: (i) although it used to be The relationship of the type of CMT, demyelinating or considered that CMT4A was inherited as an autosomal axonal, with specific genes is not perfect. For instance, MPZ recessive disorder, some mutations may be expressed mutations are usually manifested clinically as an autosomal in heterozygous patients and segregate dominantly in dominant demyelinating neuropathy, CMT1B.67 However, some families; (ii) GDAP1 mutations are relatively some mutations in MPZ have also been found in patients with frequent in our population, thus, the gene could be 89 axonal neuropathy (CMT2-P0). Moreover, some patients included in the routine genetic testing of CMT with mutation in MPZ expressed the disease as either DSN or regardless of the inheritance pattern; and (iii) the most 10 11 CHN. On the other hand, mutations in the same gene may frequent mutation, Q163X, is the result of a founder be expressed with a different Mendelian pattern. Mutations effect as the consequence of a unique origin. in the PMP22 gene are expressed as dominant mutations, but there are some mutations in PMP22 that convey an autosomal recessive trait.12 13 CMT disease caused by mutations in the ganglioside- induced differentiation-associated protein 1 (GDAP1) gene is a severe autosomal recessive neuropathy originally reported Abbreviations: CHN, congenital hypomyelinating neuropathy; CMAP, in families with either demyelinating CMT4A neuropathy compound motor action potential; CMT disease, Charcot-Marie-Tooth 14 15 (MIM 214400) or axonal neuropathy with vocal cord disease; DSN, De´je´rine-Sottas neuropathy; NCVs, nerve conduction paresis (MIM 607706),16 which maps to the CMT4A locus on velocities; SNAP, sensory nerve action potential www.jmedgenet.com Letter to JMG 359 chromosome 8q21.1. GDAP1 is a 358 amino acid protein dideoxynucleotides and one of the PCR primers. All whose function is not well known. It is expressed in both the sequences on both strands were determined. J Med Genet: first published as 10.1136/jmg.2004.022178 on 1 April 2005. Downloaded from central and peripheral nervous system.16 17 A putative role as glutathione S-transferases has been postulated for Microsatellite and SNP genotyping GDAP1.16 17 Genotyping for the six microsatellite markers linked to the Mutations in the GDAP1 gene have been observed CMT4A locus was performed using a similar PCR protocol: particularly in patients from Mediterranean countries,15 16 18–22 4 min initial denaturation at 95˚C, 35 cycles of 30 s but also in those from other European regions.15 23 24 The most denaturation at 94˚C, 30 s annealing and elongation at 55˚C prevalent mutation in Spain is Q163X,16 which has also been (D8S279, D8S286, and D8S551)or58˚C(D8S1474, D8S1289, found in three North American Hispanic families.25 Moreover, and D8S84), and a 7 min final extension at 72˚C. PCR S194X, the most frequent mutation in North African products were run on a 12% non-denaturing polyacrylamide countries—Morocco, Tunisia15 19 21—has also been found in gel at 800 V for 10 h at room temperature. Allele fragments Spain.16 Haplotype analysis of one Moroccan family and one were visualised by silver staining. Allelic numbers for every Spanish family suggested a common origin of the S194X marker except D8S1474 are according to the Genome mutation found in both countries.18 Database (http://www.gdb.org/). D8S1474 alleles and fre- We report here the genetics of CMT4A investigated quencies were established in the general Spanish population. through genetic analysis of the GDAP1 gene and locus in a The determination of haplotype phase was based either on series 125 isolated or familial CMT patients with Spanish homozygosity or on analysis of parental samples, which ancestry. We show that the most frequent mutation, Q163X, allowed us to fully or partially define the phase. has a common origin in families from both Spain and North Analysis of the c.507T/G single nucleotide polymorphism America. We also present genetic data suggesting that (SNP) was performed by PCR amplification of exon 4 and CMT4A displays both autosomal recessive and autosomal restriction digestion with DdeI. After digestion the presence of dominant inheritance, and we document a possible correla- two bands of 168 and 120 bp indicates allele T, whereas a tion between the severity of the disease and genetic status. 288 bp undigested band indicates allele G. Both rs1025928 and rs959424 SNPs (UCSC Human Genome Browser, Human Genome Working Draft, http://genome.ucsc.edu/goldenPath/ METHODS septTracks.html) were investigated by SSCP analysis. Patients Estimation of Q163X mutation age was performed by A cohort of 161 patients belonging to 125 families with means of the maximum likelihood method implemented in Spanish ancestry and with a diagnosis of CMT disease, either the program BDMC21 v2.1 (available at http://www.rannala. axonal or demyelinating, was available for genetic analysis of org/labpages/software.html).27 The program parameter set- GDAP1. The cohort was distributed as follows: 106 isolated ting we used were: growth rate = 0.005, sample fraction = cases, 13 families with autosomal recessive inheritance 0.0000325 (assuming a carrier frequency of 1/200 in the (categorised thus because more than one sib was affected general population, a total population size of 40 million and parents were normal by examination or history), and six individuals, and a mutation rate of short tandem repeat families with autosomal dominant inheritance. Consan- (STR) linked markers of 0.0001). Program data settings were: guinity was observed in 10 isolated cases and three families. 13 mutant copies, which are the mutant alleles in our sample, In all cases mutations in the PMP22, MPZ, and GJB1 genes 16 and two segregating sites. Program option settings were: had previously been excluded. Mutation analysis and conditional on copy number = yes, number of Monte Carlo http://jmg.bmj.com/ 26 clinical descriptions for families LF38, LF249, and LF20 replicates = 10 000, initial time = 10, final time = 500, and has previously been reported. Mutation studies and clinical interval increments = 10. data of the Hispanic families HOU531, HOU364, and Exclusion of false paternity was performed by using 10 25 HOU726, have also been reported elsewhere.
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