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.

摘要: The Charcot-Marie-Tooth (CMT) disorders comprise a group of clinically and genetically heterogeneous hereditary motor sensory neuropathies, which are mainly characterized by muscle weakness wasting, foot deformities, electrophysiological, as well histological, changes. A subtype, CMT2, is defined slight or absent reduction nerve-conduction velocities together with the loss large myelinated fibers axonal degeneration. CMT2 phenotypes also genetic heterogeneity, although only two genes—NF-L KIF1Bβ—have been identified to date. Homozygosity mapping in inbred Algerian families autosomal recessive (AR-CMT2) provided evidence linkage chromosome 1q21.2-q21.3 (Zmax=4.14). All patients shared common homozygous ancestral haplotype that was suggestive founder mutation cause phenotype. unique LMNA (which encodes lamin A/C, component nuclear envelope) all affected members additional from third, unrelated family. Ultrastructural exploration sciatic nerves null (i.e., −/−) mice performed revealed strong axon density, enlargement, presence nonmyelinated axons, were highly similar human peripheral axonopathies. finding site-specific amino acid substitutions limb-girdle muscular dystrophy type 1B, dominant Emery-Dreifuss dystrophy, dilated cardiomyopathy 1A, partial lipodystrophy, and, now, AR-CMT2 suggests existence distinct functional domains A/C essential for maintenance integrity different cell lineages. To our knowledge, this report constitutes first inheritance causes CMT2; additionally, we suggest mutations may be overlapping disorder CMT2B1.