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.
