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

Am J Hum Genet. 2002 Mar;70(3):726-36. doi: 10.1086/339274. Epub 2002 Jan 17.


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 (Zmax=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 exploration 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algeria
  • Amino Acid Sequence
  • Animals
  • Arginine / genetics
  • Axons / pathology*
  • Axons / ultrastructure
  • Base Sequence
  • Charcot-Marie-Tooth Disease / classification
  • Charcot-Marie-Tooth Disease / genetics*
  • Charcot-Marie-Tooth Disease / pathology*
  • Consanguinity
  • Conserved Sequence
  • Electrophysiology
  • Exons / genetics
  • Female
  • Genes, Recessive / genetics*
  • Homozygote*
  • Humans
  • Lamin Type A
  • Lamins
  • Linkage Disequilibrium / genetics
  • Male
  • Mice
  • Mice, Knockout
  • Molecular Sequence Data
  • Mutation / genetics
  • Nuclear Envelope / chemistry*
  • Nuclear Proteins / analysis
  • Nuclear Proteins / genetics*
  • Pedigree
  • Sciatic Nerve / pathology
  • Sciatic Nerve / ultrastructure


  • Lamin Type A
  • Lamins
  • Nuclear Proteins
  • Arginine

Associated data

  • GENBANK/AF188240
  • GENBANK/AK022349
  • GENBANK/P08928
  • GENBANK/P11048
  • GENBANK/P13648
  • GENBANK/P48678
  • GENBANK/S42257
  • GENBANK/X85991
  • OMIM/115200
  • OMIM/118200
  • OMIM/118210
  • OMIM/145900
  • OMIM/151660
  • OMIM/159001
  • OMIM/162280
  • OMIM/181350
  • OMIM/605253
  • OMIM/605588
  • OMIM/605589
  • RefSeq/NT_004858