Laminopathies are genetic disorders caused by mutations in the lamin family of nuclear proteins, lamin A/C. The LMNA gene encodes several lamin proteins, which are classified as type V intermediate filaments and make up the nuclear membrane. The various disorders include types of muscular dystrophy, progeria, lipodystrophy, and other diseases affecting the skeleton and heart muscle, each manifesting due to a particular mutation. The disorders are rare, with each mutation being even more rare, but they can be dominant or recessive, autosomal or X-linked, and inherited or de novo. DNA testing is offered by some facilities for these disorders.
LMNA maps to chromosome 1q21 or q22, depending on the reference, and has twelve exons. Alternative splicing allows multiple isoforms of lamin A, including lamin C. Mutations in a gene sequence involve the addition or removal of nucleotides (insertions and deletions), as well as changes in the nucleotide present at a given position (point mutations). Genomic mutations may or may not affect the protein sequence, length, structure, and/or function. The Universal Mutation Database notes 408 different LMNA mutations identified in 1601 subjects, with 266 protein variants of lamin A/C.
The first mutation causing a laminopathy was identified in autosomal dominant Emery-Dreifuss muscular dystrophy in 1999. Since that time, multiple LMNA mutations have been identified in patients with this disorder, including missense mutations, splice site mutations, insertions, and deletions. The National Institutes of Health Genetics Reference notes that more than 100 mutations have been identified in patients with Emery-Dreifuss, most affecting the protein sequence.
Over the past 12 years, numerous other mutation-disorder associations have been made, sometimes in as few as a single patient:
Limb girdle muscular dystrophy - allelic variation on chromosome 1q11-q21 encompassing missense, codon deletion, and splice site mutations, with at least six different mutations identified
Autosomal dominant dilated cardiomyopathy and conduction-system disease - five missense mutations translating to protein changes, four affecting the helical-rod domain of lamin A/C and one affecting the lamin C tail
Autosomal recessive (type 2B1) Charcot-Marie-Tooth disease - homozygous R298C mutation (arginine replaced by cysteine at position 298 in the amino acid sequence of the protein)
Dunnigan type familial partial lipodystrophy - R482Q or codon R486
Mandibuloacral dysplasia - homozygous R527H (caused by G1580A gene mutation), histidine replaces arginine in the protein; S573L (caused by C1718T gene mutation in exon 11)
Childhood progeria, Hutchinson-Gilford syndrome - C1824T (thymine replaces cytosine in the gene sequence), causing G608G, a deletion of a portion of the protein, forming the aberrant lamin A protein progerin
Atypical Werner’s syndrome – R133L (leucine replaces arginine)
Restrictive dermopathy - complete or partial deletion of exon 11
Mutations may occur in other genes and disrupt the function of lamins, causing laminopathy – these are secondary laminopathies, as opposed to primary laminopathies caused by mutations in LMNA and/or lamin A/C. Mutation of the gene encoding another nuclear protein, emerin, is associated with laminopathic muscular dystrophy. Similarly, the appearance of atypical Werner’s syndrome has been associated with mutation of the RECQL2 gene. Mandibuloacral dysplasia has been associated with compound mutations in the zinc metalloprotease (ZMPSTE24) gene: Phe361fsX379 and Trp340Arg. This gene is also found to have recessive null mutations (in exon 9) in restrictive dermopathy, a lethal laminopathy causing death in infancy.
Research into these disorders and their causative mutations is ongoing. The rarity of the disorders makes them difficult to study in large cohorts, and individuals can have novel mutations. In addition, the lifespan of some of the patients are too short to carry out appropriate investigations to pinpoint the mechanisms underlying laminopathy.