Devastating genetics: Laminopathies

Structure of the nuclear lamina. Source: Coutinho et al. CC2.0

Laminopathies are genetic conditions caused by defects in lamin A/C, commonly caused by mutations in LMNA and other genes. The lamins make up the protein matrix adjacent to the inner nuclear membrane. Thus, laminopathies are a type of nuclear envelopathy. 

Nuclear envelopathies

The nuclear envelope is an important structure in the eukaryotic cell. It not only partitions the nucleus from the rest of the cell, but it has also been found in recent years to be involved in mitotic processes. The nuclear envelope is composed of the two-layer nuclear membrane and nuclear pore structures – all of which require proteins. Defects in the genes encoding these proteins have been termed nuclear envelopathies.

In 2005, Somech et al. wrote an extensive review of what was known about nuclear envelopathies at the time for the journal Pediatric Research. At that time, four proteins were known to be mutated in these diseases: emerin, lamin A/C, lamin B receptor, and MAN1, a lamin-associated protein encoded by the LEMD3 gene. By 2009, defects in the SUN proteins had also been implicated in disrupted nuclear position, and the ZMPST24 gene, which encodes a protein that processes lamin A, had been implicated in lamin-associated disorders.

 

Laminopathies

The most well known nuclear envelopathies are laminopathies. The lamins form the lamina, a complex of intermediate filaments under the inner nuclear membrane that connect nuclear pore complexes. Some researchers, such as Broers et al. in 2006, differentiate laminopathies from nuclear envelopathies, defining the envelopathies as defects in the inner nuclear membrane and nuclear pore complex only. Laminopathies result in numerous types of disorders, at least a dozen that have been named and recognized, including premature aging, muscular dystrophy, lipodystrophy, and cardiovascular disorders.

Emerin is encoded by the EMD gene. Defects in this gene are now termed emerinopathies. Defects in EMD and LMNA cause similar muscular dystrophic disorders. Defects in the lamin B receptors (encoded by the LMNB gene) cause chromatin disorders in blood granulocytes, termed Pelger-Huet anomaly.

 

Other nuclear envelope defects

Other recent additions to the list of nuclear envelope defects are the SYNE1 gene, encoding Nesprin-1 and causing cerebellar ataxia; TOR1A gene encoding TorsinA and causing dystonia; AAAS gene encoding Aladin and causing triple-A syndrome; and defects in the nuclear pore complex. The nuclear pore defects, called nucleoporinopathies, are related to Nup155, Nup62, and RanBP2, causing atrial fibrillation, infantile striatal necrosis, and acute necrotizing encephalopathy, respectively. Work in mice has also indicated that mitotic arrest deficient (MAD) proteins, which are associated with the nuclear pore, may cause defects in mitosis, allowing tumor cell growth.

Nuclear envelopathies are congenital defects, and as such require consultation with a genetic counselor for treatment options. Some of the mutations are inherited, yet others are de novo mutations (occurring spontaneously prior to or during embryological development). Genetic testing can pinpoint the exact cause of suspected nuclear envelopathy in many cases, but research is ongoing as to the best diagnosis and treatment options.

Mutations in LMNA

Mutations in the LMNA gene result in destabilization of the nuclear envelope, disrupted chromatin structure, and interrupted gene expression. The gene encodes three protein isoforms, so mutations can have a broad range of effects, specific tissues or more generalized, depending on the exact mutation, and the list includes progeria, muscular dystrophy, Charcot-Marie-Tooth, and lipodystrophy.

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.

Primary laminopathies

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. Restrictive dermopathy is a rare, autosomal recessive laminopathy that causes skin and bone dysplasia. The disorder is lethal in infancy due to respiratory complications. It can be caused not only by mutations in LMNA, but also an associated gene (secondary laminopathy).

Secondary laminopathies

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.

Muscular dystrophy

Muscular dystrophy is a progressive loss of muscle tissue and strength (atrophy). Mutation of lamin A/C is involved in at least two forms of this genetic disease: Emery-Dreifuss type 2 and limb girdle type 1B.

Emery-Dreifuss muscular dystrophy type 2 is an inherited condition (X-linked recessive according to Cleveland Clinic though other reports indicate a dominant form, type 3) that affects both skeletal and cardiac muscle. The earliest symptom is joint contractures, which restrict movement and often appear during childhood. Heart rhythm problems become apparent in adulthood. The other forms of Emery-Dreifuss muscular dystrophy are related to the emerin (EMD) gene (emerinopathy) and more common than those related to the LMNA gene. Studies have spent considerable effort in differentiating these forms of the disease.

Limb girdle muscular dystrophy affects the proximal muscles of the body, those closest to the center: the shoulders and hips. Only one of the 19 known forms of this disorder is a laminopathy according to the Muscular Dystrophy Association, and it is autosomal dominant. Age of onset can vary, as can the speed and course of progression.

Progeria

Progeria is a premature aging syndrome, and it can manifest in either childhood or adulthood depending on the mutation that causes it.

Known as Hutchinson-Gilford syndrome, children with progeria begin to rapidly age shortly after birth and have a risk of early stroke and other heart problems. This form of progeria was first recognized as a laminopathy in 2003. It is a dominant disorder, occurring with a new mutation in lamin A in 90 percent of cases. Patients rarely survive into their teens.

Werner syndrome is known as adult-onset progeria. When individuals with the disorder hit puberty, they start aging at a rapid pace. The syndrome is most often associated with mutations in the WRN gene, but cases with LMNA mutations have been identified, dubbed atypical Werner's syndrome. Diabetes, heart disease, and other aging-related problems are often seen in these patients. Atypical Werner’s also has features of lipodystrophy.

Lipodystrophy

Lipodystrophy is atrophy of adipose tissue, resulting in abnormal fat redistribution. Familial partial lipodystrophy is characterized by a loss of subcutaneous fat in one area of the body and redistribution in another. In the most common form of the disorder, type 2, fat loss occurs in the torso and limbs with redistribution to the face and neck. Type 2, or Dunnigan-type, familial partial lipodystrophy is caused by a defect in the LMNA gene and associated with metabolic disorders like diabetes. An associated disorder is mandibuloacral dysplasia, a rare autosomal recessive disorder caused by defects in lamin A/C that causes lipodystrophy as well as aberrant skeletal development, particularly in the face and jaw.

Charcot-Marie-Tooth disorder

Charcot-Marie-Tooth disorder is considered the most common inherited nerve condition. The peripheral nerves are affected, resulting in foot deformities, weakness, and numbness with leg muscle atrophy. The disease is progressive but ranges from mild to severe, eventually leading to an inability to walk in those who are most severely affected. The defects appear in adolescence or early adulthood. The various types of Charcot-Marie-Tooth are caused by defects in different genes. Type 2B1 is a non-demyelinating form caused by mutations in LMNA. In 2009, this laminopathy was also associated with concurrent dilated cardiomyopathy when a new mutation was identified.

Heart manifestations

The manifestation of cardiac-specific laminopathy manifests as dilated cardiomyopathy with associated conduction issues and heart failure. As with other forms of the disorder, diabetes and metabolic disturbances (particularly insulin resistance) may be present. The disorder takes time to develop because dilated cardiomyopathy is a progressive weakening of the heart muscle. Another manifestation is heart-hand syndrome. It is characterized by congenital heart disease and limb deformities. In recent years, new mutations were discovered that put individuals at risk of sudden cardiac death.

As research continues into these conditions and more mutations are identified, new types of laminopathy will likely be named. The involvement of other genes is also becoming evident.