Genetic refinement and physical mapping of the CMT4B gene on chromosome 11q22

Charcot-Marie-Tooth disease type 4B (CMT4B) is a demyelinating autosomal recessive motor and sensory neuropathy characterized by focally folded myelin sheaths in the peripheral nerve. We recently mapped the CMT4B gene to a 5-cM interval on chromosome 11q22, using homozygosity mapping and haplotype sharing analysis on a large inbred pedigree. In the present study, we report the construction of a YAC-based transcript map across the 5-cM critical region, including 26 YACs, 35 STSs, and 52 ESTs. Furthermore, using 15 additional physically ordered microsatellite markers from the 11q22 region on the original inbred family, we were able to narrow the critical interval for the gene to 2 Mb, which is now flanked by markers D11S1757 and CHLC-GATA3B05. Finally, after computer analysis of the 33 ESTs assigned to the 2-Mb interval, we demonstrated that 21 different transcripts as well as 3 known genes might represent potential candidates for the disease.

[1]  E. Mariman,et al.  Two divergent types of nerve pathology in patients with different P sub 0 mutations in Charcot-Marie-Tooth disease , 1996, Neurology.

[2]  J. Weber,et al.  Abundant class of human DNA polymorphisms which can be typed using the polymerase chain reaction. , 1989, American journal of human genetics.

[3]  C. Broeckhoven,et al.  Autosomal recessive hereditary motor and sensory neuropathy with focally folded myelin sheaths: clinical, electrophysiologic, and genetic aspects of a large family. , 1996, Neurology.

[4]  C. van Broeckhoven,et al.  The Thr124Met mutation in the peripheral myelin protein zero (MPZ) gene is associated with a clinically distinct Charcot-Marie-Tooth phenotype. , 1999, Brain : a journal of neurology.

[5]  A. Monaco,et al.  Refined genetic mapping of the darier locus to a <1-cM region of chromosome 12q24.1, and construction of a complete, high-resolution P1 artificial chromosome/bacterial artificial chromosome contig of the critical region. , 1998, American journal of human genetics.

[6]  P. Lijnzaad,et al.  A physical map of 30,000 human genes. , 1998, Science.

[7]  J. Vance,et al.  Hereditary motor and sensory neuropathies. , 1991, Journal of medical genetics.

[8]  M. Devoto,et al.  Localization of a gene responsible for autosomal recessive demyelinating neuropathy with focally folded myelin sheaths to chromosome 11q23 by homozygosity mapping and haplotype sharing. , 1996, Human molecular genetics.

[9]  M. Suyama,et al.  Prediction of the coding sequences of unidentified human genes. XII. The complete sequences of 100 new cDNA clones from brain which code for large proteins in vitro. , 1998, DNA research : an international journal for rapid publication of reports on genes and genomes.

[10]  C. Broeckhoven,et al.  Advances in Charcot–Marie–Tooth Disease Research: Cellular Function of CMT-Related Proteins, Transgenic Animal Models, and Pathomechanisms , 1997, Neurobiology of Disease.

[11]  G. Borsani,et al.  How to get the best of dbEST. , 1998, Trends in genetics : TIG.

[12]  P. Deloukas,et al.  A Gene Map of the Human Genome , 1996, Science.

[13]  A. Brice,et al.  Homozygosity Mapping of an Autosomal Recessive Form of Demyelinating Charcot-Marie-Tooth Disease to Chromosome 5q23–q33 , 1996 .

[14]  J. Lupski,et al.  Mutations in the early growth response 2 (EGR2) gene are associated with hereditary myelinopathies , 1998, Nature Genetics.

[15]  N. Nomura,et al.  Prediction of the coding sequences of unidentified human genes. VII. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro. , 1997, DNA research : an international journal for rapid publication of reports on genes and genomes.

[16]  A. Schenone,et al.  Hereditary motor and sensory neuropathy with myelin outfolding: Clinical, genetic and neuropathological study of three cases , 1994, Journal of the Neurological Sciences.

[17]  M V Olson,et al.  Systematic screening of yeast artificial-chromosome libraries by use of the polymerase chain reaction. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[18]  E. Myers,et al.  Basic local alignment search tool. , 1990, Journal of molecular biology.

[19]  M. Devoto,et al.  Genetic heterogeneity in autosomal recessive hereditary motor and sensory neuropathy with focally folded myelin sheaths (CMT4B) , 1998, Neurology.

[20]  A. Hristova,et al.  Gene mapping in Gypsies identifies a novel demyelinating neuropathy on chromosome 8q24 , 1996, Nature Genetics.

[21]  N. Nomura,et al.  Prediction of the coding sequences of unidentified human genes. IV. The coding sequences of 40 new genes (KIAA0121-KIAA0160) deduced by analysis of cDNA clones from human cell line KG-1. , 1995, DNA research : an international journal for rapid publication of reports on genes and genomes.

[22]  A. Sureau,et al.  Characterization of SRp46, a Novel Human SR Splicing Factor Encoded by a PR264/SC35 Retropseudogene , 1998, Molecular and Cellular Biology.

[23]  A. Brice,et al.  Autosomal recessive hereditary neuropathy with focally folded myelin sheaths and linked to chromosome 11q23: a distinct and homogeneous entity , 2000, Neuromuscular Disorders.

[24]  A. Gambardella,et al.  Hereditary demyelinating neuropathy of infancy: a genetically complex syndrome. , 1997, Brain : a journal of neurology.

[25]  M. Pericak-Vance,et al.  Linkage of a locus (CMT4A) for autosomal recessive Charcot-Marie-Tooth disease to chromosome 8q. , 1993, Human molecular genetics.

[26]  S. Sakoda,et al.  A novel MPZ gene mutation in dominantly inherited neuropathy with focally folded myelin sheaths , 1999, Neurology.

[27]  C. van Broeckhoven,et al.  Mutations in the peripheral myelin genes and associated genes in inherited peripheral neuropathies , 1999, Human mutation.