OBJECTIVE: To identify the molecular basis of a demyelinating Charcot-Marie-Tooth disease type 1 (CMT1) with presumed autosomal recessive inheritance. BACKGROUND: CMT1, an inherited motor and sensory neuropathy with low nerve conduction velocities, is caused by dominantly inherited mutations in the genes of the peripheral myelin protein 22 (PMP22), myelin protein zero (MPZ/P(0)), and early growth response 2 transcription factor (EGR2/Krox-20). PATIENTS AND METHODS: Two young sisters born of clinically and electrophysiologically healthy parents had a severe CMT1 neuropathy of presumed autosomal recessive inheritance. The older sister underwent a nerve biopsy. The authors analyzed PMP22, MPZ/P(0), and EGR2/Krox-20 by automated direct nucleotide sequencing. For rapid mutation detection, they determined the restriction-fragment-length polymorphisms for TaqI in the fluorescein-labeled target DNA sequence amplified by PCR. RESULTS: Nerve biopsy disclosed a demyelinating and remyelinating neuropathy with onion bulb formations. Both sisters had a novel heterozygous G308-->A transition of MPZ/P(0) without any mutation of PMP22 or EGR2/Krox-20. The G308-->A transition was a nonconservative mutation that changed a glycine into a glutamate at the amino acid residue 74 in the extracellular domain of the mature MPZ/P(0). None of 50 healthy controls had the mutation. The healthy mother had a low amount of the mutation in blood (congruent with 20%) as well as in skin, buccal epithelium, and hairs (30%). Because the healthy mother carried clones of somatic mutant cells and had transmitted the G308-->A transition to the affected daughters, she also harbored germline mutant cells. CONCLUSION: In hereditary demyelinating neuropathies, somatic and germline mosaicism of dominant mutations in the myelin protein genes may mimic autosomal recessive inheritance.
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