Lee, Ming-Jen; (2003) Genetic analysis of hereditary sensory, motor and autonomic neuropathies, including a rat model. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

The subject of this thesis is genetic research in two inherited neuropathies, the hereditary sensory and autonomic neuropathies (HSAN) and Charcot-Marie-Tooth diseases (CMTs). Two sections are included; the first is dedicated to identifying the causative gene of a hereditary sensory neuropathy in a spontaneous mutant rat (mf rat). The second involves the sequencing of two known genes in patients with CMTs. The locus for the mf disease was linked to the distal end of rat chromosome 14. Using the sequences of the closely linked rat microsatellite markers, database BLAST searches identified a three Megabase region on mouse chromosome 11 whose gene content was co-linear with that on human 2p15-p16. Sequencing the cDNA of genes in this interval revealed a c.1349G>A substitution in subunit 4 of the chaperonin containing TCP-1 protein (Cct4) in the mutant rat. This change replaced a highly conserved cysteine450 with tyrosine. This result demonstrates that a mutation in the Cct4 protein causes an inherited sensory neuropathy in rats. The genes, myelin protein zero (MPZ) and gap junction protein beta1 (GJB1), were screened for mutations in patients with CMT. Most forms of CMT are either clearly demyelinating or axonal. Mutations in MPZ and GJB1 can cause both types of CMT. Two novel MPZ mutations were identified in five Taiwanese patients with a demyelinating neuropathy. Forty-six British patients with axonal CMT were also screened but only one mutation was identified. The frequency of MPZ mutations in axonal CMT is low. GJB1 is the gene responsible for X-linked CMT (CMTX). The clinical features of CMTX patients are variable and the neurophysiological findings can suggest a demyelinating or an axonal neuropathy. 24 mutations (6 novel ones) were identified in 139 patients with CMT. Detailed clinical and electrophysiological studies in these patients are presented. In conclusion, this thesis identified the genetic defect of the mf rat, an animal model for HSAN, and identified mutations in MPZ and GJB1 in CMT patients.

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