Hum Genet (1991) 88:1-12 Original investigations 9 Springer-Verlag 1991 Chromosome 1 Charcot-Marie-Tooth disease (CMTIB) locus in the Fc7 receptor gene region Roger V. Lebo l, Phillip F. Chance 2, Peter J. Dyck 3, Ma. Theresa Redila-Flores l, Eric D. Lynch 1, Mitchel Thomas D. Bird 4, Mary Claire King 5, Lee A. Anderson 1'5, Jeffrey Hall 5, Joop Wiegant 6, Zharong Jiang l, Paul F. Dazin l, Hope H. Punnett 7, Steven A. Schonberg l, Kevin Moore 8, Marcia M. Shull 9, Sandra Ge Orest Hurko 11, Robert E. Lovelace 12, Norman Latov 12, James Trofatter 13, and P. Michael Conneally 1 1Departments of Obstetrics, Gynecology, and Pediatrics, U-262, University of California, San Francisco, CA 94143-0720, USA ZDepartment oiPediatrics, University of Utah, Salt Lake City, Utah, USA 3Department of Neurology, Mayo Clinic, Rochester, Minnesota, USA 4Department of Neurology, University of Washington, Seattle, Washington, USA 5 School of Public Health, University of California, Berkeley, California, USA 6Department of Histochemistry and Cytochemistry, Leiden University, Leiden, The Netherlands 7 St. Christopher's Hospital for Children, Philadelphia, Pennsylvania, USA aDNAX Institute of Molecular and Cellular Biology, Palo Alto, California, USA 9 Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati, Ohio, USA 1~ Cancer Research Fund, London, UK 11 Department of Neurochemistry, Johns Hopkins, Baltimore, Maryland, USA 12Department of Neurology, Columbia University, New York, New York, USA 13Department of Medical Genetics, University of Indiana, Indianapolis, Indiana, USA Received November 27, 1990 / Revised March 7, 1991 Summary. The Charcot-Marie-Tooth disease (heredit- ary motor and sensory neuropathy) loci have been re- ported to be on at least three chromosomes: 1 (CMT1B, HMSNIB), 17 (CMT1A), and X (CMTX). In this study multipoint linkage analysis of two Duffy-linked families given a combined LOD score of 8.65 to establish that the Duff-y-linked CMT1B gene exists in the 18 centimorgan region between the antithrombin III gene and the Dully/ sodium-potassium ATPase loci. The simultaneous segre- gation of polymorphisms near the CMTIA locus on chro- mosome 17 excludes linkage to this chromosome region in both families. Polymorphic sites that flank the CMT1B gene have been subchromosomally localized to the prox- imal chromosome-1 long arm (lq21.2---,lq25) by spot blot analysis of sorted chromosomes, polymorphic dele- tion analysis, in situ hybridization, and multipoint link- age analysis. Introduction Charcot-Marie-Tooth (CMT) disease, also called heredi- tary motor and sensory neuropathy (HMSN) or peroneal muscular atrophy, is a worldwide problem that causes distal muscle weakness and atrophy and peripheral nerve hypertrophy in affected patients (Lovelace and Shapiro 1990). The incidence in western Norway was reported to be 1/2600 for autosomal dominant; 1/26,000 for autoso- Offprint requests to: R.V. Lebo mal recessive; and 1/72,000 for X-linked CMT diseas (Skre 1974). A similar autosomal dominant frequency has been reported in Spain (Berciano et al. 1986). These prevalence figures are undoubtedly low because undiag- nosed neuropathy frequently can be shown to be inher- ited, mild cases go undetected, and others are probably diagnosed incorrectly. The CMT subtypes are clinically similar but geneti- cally heterogeneous with different patterns of natural history and clinical electrophysiology. The disease sub- types share abnormal foot structures including pes cavus distal muscle wasting and atrophy, mild sensory loss, and autonomic disturbances. Abnormalities ar e symmetrical and more severe in the lower limbs. Hereditary motor and sensory neuropathy has been subdivided into tw types based on motor nerve conduction velocity. Type I (HMSN1, CMT1) is a demyelinating neuropathy with prolonged motor nerve conduction velocities and hyper- trophic changes on peripheral nerve histology. Type II (HMSN2, CMT2) is a nondemyelinating neuronal disor- der with normal or near normal motor nerve conduction velocities without hypertrophic changes. (Dyck and Lam- bert 1968a, b; Dyck 1984).The CMT1 disorders are manifested in childhood or adolescence and progress slowly but inexorably (Bird and Kraft 1978; Vanasse and Dubowitz 1981). CMT disease gene loci have been reported to reside on at least three chromosomes. A slow nerve conduction velocity dominant CMT1 (HMSN1; Bird et al. 1980, 1982;Guiloff et al. 1982) gave a combined two-point LOD score with the Dully blood group locus of 3.02 at