The clinical outcome of LMNA missense mutations can be associated with the amount of mutated protein in the nuclear envelope

Abstract

The clinical findings indicated that some LMNA mutations may be associated with a favourable prognosis and a low risk of sudden death. Protein expression studies suggested that a severe outcome was associated with the expression of high amounts of mutated protein. These findings may prove to be helpful in counselling and risk assessment of LMNA families.

October 2018 at a glance: from demographic variables to genotype–phenotype interactions

“…In contrast, two smaller families with severe disease expression and poor outcomes had different LMNA mutations with a higher mutated to wild‐type protein ratio (50:50). This study shows that, differently than generally believed, LMNA mutations may be associated also with a benign clinical course and the amounts of mutated protein may be related with disease severity and outcomes …”

Lamin missense mutations—the spectrum of phenotype variability is increasing

“…However, families may be characterized by a limited number of members available for segregation studies (e.g. the LMNA ‐p.Arg471Cys and LMNA ‐p.Arg471His reported by Al‐Saaidi et al D and E ); patients may have been adopted, or there may be other reasons that limit segregation studies ( Figure F and G ).…”

“…It is reasonable to postulate that the ‘malignancy’ or penetrance of a given mutation may depend on (or be related with) the mutated residue in terms of its impact on protein folding, dimerization, and intermolecular interactions as hinted to above. But what is more puzzling is that even when mutational invariance appears absolute, phenotypic pleiotropy still abounds: for example, the LMNA ‐p.Arg471Cys was associated with aggressive DCM and SCD, but just recently Florwick et al . identified the same mutation in three unrelated asymptomatic ExAC cohort participants.…”

“…When myocardial samples are unavailable, fibroblasts derived from skin biopsies of mutation carriers are an easy alternative source of cells that can be used to measure the transcripts of the mutated gene via quantitative reverse transcriptase polymerase chain reaction (qRT‐PCR), mutated and non‐mutated protein expression (Western blotting), presence and distribution of the mutated lamin in cell nuclei (immunohistochemistry), and quantitative amount of the mutated lamin using protein mass spectrometry. In the larger family with LMNA ‐p.Arg216Cys mutation (more favourable phenotype) reported by Al‐Saaidi et al ., mutated patients expressed less mutant lamin compared to wild‐type protein (30:70 mut/wt), whilst carriers of LMNA ‐p.Arg471Cys and LMNA ‐p.Arg471His mutations (more adverse phenotypes) expressed considerably more mutant lamin relative to wild‐type (50:50 mut/wt). Open questions may remain, such as for example whether LMNA point mutations suffice to explain the observed discrepancy in mut/wt lamin protein levels.…”

“…The counter proposition is that CCD is the only clinically expressed trait in some cardiolaminopathies, or that the main clinical manifestations are supraventricular arrhythmias with CCD ( Figure B ). In family A described by Al‐Saaidi et al ., the member III‐7 clinically opens with atrioventricular block (AVB) + left bundle branch block aged 62 years at which point he receives a permanent pacemaker but develops atrial fibrillation at 73 years and dies aged 74 from a stroke without ever apparently developing DCM. Family A member IV‐6 manifests only AVB and does not develop DCM in the ensuing 5 years; member IV‐10, with CCD and atrial fibrillation, presents with limb‐girdle muscular dystrophy but not DCM.…”