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Homozygous Defects In Lmna, Encoding Lamin A/C Nuclear‐Envelope Proteins, Cause Autosomal Recessive Axonal Neuropathy In Human (Charcot‐Marie‐Tooth Disorder Type 2) And Mouse

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The Charcot‐Marie‐Tooth (CMT) disorders comprise a group of clinically and genetically heterogeneous hereditary motor and sensory neuropathies, which are mainly characterized by muscle weakness and wasting, foot deformities, and electrophysiological, as well as histological, changes. A subtype, CMT2, is defined by a slight or absent reduction of nerve‐conduction velocities together with the loss of large myelinated fibers and axonal degeneration. CMT2 phenotypes are also characterized by a large genetic heterogeneity, although only two genes‐NF‐L and KIF1Bbeta‐have been identified to date. Homozygosity mapping in inbred Algerian families with autosomal recessive CMT2 (AR‐CMT2) provided evidence of linkage to chromosome 1q21.2‐q21.3 in two families (Z(max) = 4.14). All patients shared a common homozygous ancestral haplotype that was suggestive of a founder mutation as the cause of the phenotype. A unique homozygous mutation in LMNA (which encodes lamin A/C, a component of the nuclear envelope) was identified in all affected members and in additional patients with CMT2 from a third, unrelated family. Ultrastructural explor‐ ation of sciatic nerves of LMNA null (i.e., −/−) mice was performed and revealed a strong reduction of axon density, axonal enlargement, and the presence of nonmyelinated axons, all of which were highly similar to the phenotypes of human peripheral axonopathies. The finding of site‐specific amino acid substitutions in limb‐girdle muscular dystrophy type 1B, autosomal dominant Emery‐Dreifuss muscular dystrophy, dilated cardiomyopathy type 1A, autosomal dominant partial lipodystrophy, and, now, AR‐CMT2 suggests the existence of distinct functional domains in lamin A/C that are essential for the maintenance and integrity of different cell lineages. To our knowledge, this report constitutes the first evidence of the recessive inheritance of a mutation that causes CMT2; additionally, we suggest that mutations in LMNA may also be the cause of the genetically overlapping disorder CMT2B1.
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Document Type: Research Article

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Publication date: September 1, 2002

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