Clinical and genetic heterogeneity in laminopathies

Abstract

Mutations in the LMNA gene encoding lamins A/C are responsible for more than ten different disorders called laminopathies which affect various tissues in an isolated (striated muscle, adipose tissue or peripheral nerve) or systemic (premature aging syndromes) fashion. Overlapping phenotypes are also observed. Associated with this wide clinical variability, there is also a large genetic heterogeneity, with 408 different mutations being reported to date. Whereas a few hotspot mutations emerge for some types of laminopathies, relationships between genotypes and phenotypes remain poor for laminopathies affecting the striated muscles. In addition, there is important intrafamilial variability, explained only in a few cases by digenism, thus suggesting an additional contribution from modifier genes. In this regard, a chromosomal region linked to the variability in the age at onset of myopathic symptoms in striated muscle laminopathies has recently been identified. This locus is currently under investigation to identify modifier variants responsible for this variability.

Cellular micro-environments reveal defective mechanosensing responses and elevated YAP signaling in LMNA-mutated muscle precursors

“…Conflicting results have been reported regarding the cytoskeletal architecture in lamin-deficient cells, which has been found to be either almost unaffected (Lammerding et al, 2004;Lee et al, 2007;Hale et al, 2008) or disturbed (Khatau et al, 2009;Kim et al, 2012). Moreover, unlike the mouse and cellular models, which often require homozygous expression of the mutant lamin A/C (Worman and Bonne, 2007;Bertrand et al, 2011), human cells from LMNA-related muscular dystrophy carry only one mutated LMNA allele and therefore also express wild-type lamin.…”

“…This physical sensing mechanism involves a mechanical link between the extracellular matrix (ECM) and the nucleus through a complex network that involves cell adhesion sites, actinmyosin contractile apparatus and the nucleoskeleton (Geiger et al, 2009), of which lamins are the major component (Méjat and Misteli, 2010;Simon and Wilson, 2011). Mutations in the LMNA gene, which encodes for A-type lamins (lamin A/C), cause laminopathies, a highly heterogeneous group of disorders, including muscular dystrophies and cardiomyopathies (Worman and Bonne, 2007;Bertrand et al, 2011). The severity of the skeletal muscle myopathy is highly variable, the most severe being the LMNA-related congenital muscular dystrophy (L-CMD), that is characterized by an early onset of muscle hypotonia and weakness, joint contractures, spinal stiffness and respiratory involvement (Quijano-Roy et al, 2008).…”

Novel homozygous missense variant of GRIN1 in two sibs with intellectual disability and autistic features without epilepsy

“…This gene is associated with about 15 different diseases including Emery-Dreifuss muscular dystrophy, limb-girdle muscular dystrophy type 1B and Huntchinson-Gilford progeria that mostly follow an autosomal-dominant mode of inheritance, and CharcotMarie-Tooth disease type 2B1 that is an autosomal recessive disorder. 7 In the field of epilepsy, such a situation has also been observed for several genes. Some variants in POLG are found in families with autosomal-dominant progressive external ophtalmoplegia, whereas other variants cause a range of autosomal-recessive conditions including Alpers syndrome, mitochondrial neurogastrointestinal encephalopathy, or sensory ataxic neuropathy, dysarthria, and ophtalmoparesis syndrome.…”

Deletion of MLIP (Muscle-enriched A-type Lamin-interacting Protein) Leads to Cardiac Hyperactivation of Akt/Mammalian Target of Rapamycin (mTOR) and Impaired Cardiac Adaptation

“…Lamin A/C are ubiquitous proteins of the nuclear envelope. Mutations in lamin A/C give rise to a group of heterogeneous genetic disorders, collectively referred to as laminopathies, which display a large variety of complex clinical entities including skeletal and cardiac myopathies, lipodystrophy and metabolic abnormalities, neuropathy, leukodystrophy, and premature aging syndromes (4). The pathophysiologic mechanisms underlying the tissue-specific symptoms caused by mutant lamin A/C remain not fully understood.…”