title: 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.
abstract: 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.
authors.affiliation: INSERM U491, Génétique Médicale et Développement, Faculté de Médecine de la Timone, Marseille, France.
authors.forename: Annachiara
authors.initials: A
authors.lastname: De Sandre-Giovannoli
authors.forename: Malika
authors.initials: M
authors.lastname: Chaouch
authors.forename: Serguei
authors.initials: S
authors.lastname: Kozlov
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Vallat
authors.forename: Meriem
authors.initials: M
authors.lastname: Tazir
authors.forename: Nadia
authors.initials: N
authors.lastname: Kassouri
authors.forename: Pierre
authors.initials: P
authors.lastname: Szepetowski
authors.forename: Tarik
authors.initials: T
authors.lastname: Hammadouche
authors.forename: Antoon
authors.initials: A
authors.lastname: Vandenberghe
authors.forename: Colin L
authors.initials: CL
authors.lastname: Stewart
authors.forename: Djamel
authors.initials: D
authors.lastname: Grid
authors.forename: Nicolas
authors.initials: N
authors.lastname: Lévy
mesh_terms: D000462:Algeria; D000595:Amino Acid Sequence; D000818:Animals; D001120:Arginine / Q000235:genetics; D001369:Axons / Q000473:pathology* / Q000648:ultrastructure; D001483:Base Sequence; D002607:Charcot-Marie-Tooth Disease / Q000145:classification / Q000235:genetics* / Q000473:pathology*; D003241:Consanguinity; D017124:Conserved Sequence; D004594:Electrophysiology; D005091:Exons / Q000235:genetics; D005260:Female; D005808:Genes, Recessive / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D034904:Lamin Type A; D034882:Lamins; D015810:Linkage Disequilibrium / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D009685:Nuclear Envelope / Q000737:chemistry*; D009687:Nuclear Proteins / Q000032:analysis / Q000235:genetics*; D010375:Pedigree; D012584:Sciatic Nerve / Q000473:pathology / Q000648:ultrastructure
chemical_list: D034904:Lamin Type A; D034882:Lamins; D009687:Nuclear Proteins; D001120:Arginine