Phillip F. Chance

DNA deletion associated with hereditary neuropathy with liability to pressure palsies

Hereditary neuropathy with liability to pressure palsies (HNPP) is an autosomal dominant disorder that causes episodes of focal demyelinating neuropathy following minor trauma to peripheral nerves. We assign the HNPP locus to chromosome 17p11.2 and demonstrate the presence of a large interstitial deletion associated with this disorder in three unrelated pedigrees. De novo deletion is documented in one pedigree. The deleted region appears uniform in all pedigrees and includes the gene for peripheral myelin protein 22 (PMP-22), suggesting that underexpression of PMP-22 may cause HNPP. The deletion in HNPP spans approximately 1.5 Mb and includes all markers that are known to map within the Charcot-Marie-Tooth neuropathy type 1A (CMT1A) duplication. Furthermore, the breakpoints in HNPP and CMT1A map to the same intervals in 17p11.2, suggesting that these genetic disorders may be the result of reciprocal products of unequal crossover.

Trisomy 17p associated with Charcot‐Marie‐Tooth neuropathy type 1A phenotype Evidence for gene dosage as a mechanism in CMT1A

Charcot-Marie-Tooth neuropathy type 1A (CMT1A) is associated with a DNA duplication on chromosome 17, band p11.2, resulting in partial trisomy for this region in CMT1A patients. The 17p11.2 duplication may lead to the CMT1A phenotype either through disruption of a gene at the duplication breakpoint junction or by trisomie dosage and overexpression of a gene within the duplication. To test the latter model, we evaluated a patient with complete translocation trisomy 17p for signs of CMT1A. In addition to the dysmorphic features seen in trisomy 17p, a neurologic examination and electrophysiologic studies detected a demyelinating neuropathy, compatible with CMT1A. A karyotype on the patients father found a balanced translocation [t(14;17)] with breakpoints on chromosome 17 in either band p11.1 or proximal p11.2. An analysis of the patients DNA confirmed trisomy 17p and mapped the translocation breakpoint to a region in 17p11.2, proximal to the duplication breakpoint in CMT1A. Our observations in this patient with trisomy 17p are relevant to an understanding of the genetic mechanism in CMT1A and provide strong evidence that gene dosage through segmentai trisomy for 17p11.2 results in the CMT1A phenotype.

Analysis of the DNA duplication 17p11.2 in Charcot‐Marie‐Tooth neuropathy type 1 pedigrees Additional evidence for a third autosomal CMT1 locus

We have restudied two clinically typical Charcot-Marie-Tooth neuropathy type 1 (CMT1; also known as hereditary motor and sensory neuropathy 1) pedigrees that were previously reported to be unlinked to the regions of proximal chromosome 1q and chromosome 17p by multipoint linkage analyses. In these two pedigrees, there is no evidence for linkage to additional DNA markers that flank and span the CMT1A locus on chromosome 17p 11.2, and a duplication associated with CMT1A is not present in these pedigrees. These findings confirm that the CMT1 locus in these two pedigrees does not map to chromosome 17p11.2 or 1q, and provide further evidence for the existence of a third autosomal locus for CMT1.

Chromosome 1 Charcot-Marie-Tooth disease (CMT1B) locus in the Fcγ receptor gene region

Roger V. Lebo l, Phillip E Chance 2, Peter J. Dyck 3, Ma. Theresa Redila-Flores 1, Eric D. Lynch 1, Mitchell S. Golbus 1, Thomas D. Bird 4, Mary Claire King 5, Lee A. Anderson 1,5, Jeffrey Hall 5, Joop Wiegant 6, Zharong Jiang 1, Paul F. Dazin 1, Hope H. Punnett 7, Steven A. Schonberg 1, Kevin Moore s, Marcia M. Shull 9, Sandra Gendler j~ Orest Hurko ]l, Robert E. Lovelace ]2, Norman Latov 12, James Trofatter 13, P. Michael Conneally 13

Consortium Fine Localization of X-Linked Charcot-Marie-Tooth Disease (CMTX1): Additional Support that Connexin32 Is the Defect in CMTX1

Charcot-Marie-Tooth (CMT) disease is the most common form of inherited motor and sensory neuropathy. X-linked CMT (CMTX1) has been localized to the pericentric region of the X chromosome. Recently, mutations have been defined in the connexin32 gene that cosegregate with the CMTX1 phenotype in several families. The present paper presents the results of an international consortium to fine map the gene for CMTX1 to a small segment of Xq12-13. The linkage data, together with the molecular genetic studies, support the hypothesis that connexin32 is the genetic defect in CMTX1.