Genotype–phenotype correlations in laminopathies: how does fate translate?

Abstract

A-type laminopathies are a group of diseases resulting from mutations in the intermediate filament proteins lamin A and C (both encoded by the LMNA gene), but for which the pathogenic mechanisms are little understood. In some laminopathies, there is a good correlation between the presence of a specific LMNA mutation and the disease diagnosed. In others however, many different mutations can give rise to the same clinical condition, even though the mutations may be distributed throughout one, or more, of the three functionally distinct protein domains of lamin A/C. Conversely, certain mutations can cause multiple laminopathies, with related patients carrying an identical mutation even having separate diseases, often affecting different tissues. Therefore clarifying genotype-phenotype links may provide important insights into both disease penetrance and mechanism. In the present paper, we review recent developments in genotype-phenotype correlations in laminopathies and discuss the factors that could influence pathology.

A novel homozygous p.Arg527Leu LMNA mutation in two unrelated Egyptian families causes overlapping mandibuloacral dysplasia and progeria syndrome

“…In some laminopathies, there is a good correlation between the specific mutations of LMNA and the clinical manifestations of the disease; in others, multiple mutations present in distinct parts of LMNA might all result in a similar phenotype; in still other cases, the mutation of a single residue might result in a diverse phenotypes. 37 Indeed, this was also true for our patients; even though they all had the same LMNA mutation, the symptomatology of their disease was not exactly the same. First, the initial, most pronounced symptoms of the disease in the girl from Family 1, were related to the respiratory tract and appeared at the age of 2.5 years, whereas the initial symptoms in girls from Family 2 were related to the stiffness of joints and appeared at the ages of 3 and 5.…”

Deleterious assembly of the lamin A/C mutant p.S143P causes ER stress in familial dilated cardiomyopathy

“…Out of various LMNA mutations causing DCM, ∼64% are found in the rod domain (Scharner et al, 2010). The closest DCM mutations to p.S143P are p.E161K (Sebillon et al, 2003), p.N195K (Östlund et al, 2001), p.R190Q (Cowan et al, 2010) and p.R189W (Botto et al, 2010).…”

Novel LMNA mutations in patients with Emery-Dreifuss muscular dystrophy and functional characterization of four LMNA mutations

“…MAD, WRN and CMT2B1) result from 'hot spot' missense mutations. For other laminopathies including EDMD, the pathogenic LMNA mutations are distributed throughout the gene (Scharner, et al, 2010). The LMNA gene contains 12 exons and encodes both lamin A and C by alternative splicing, both sharing the first 566 amino acids (Lin and Worman, 1993).…”