A recurrent familial partial lipodystrophy due to a monoallelic or biallelic LMNA founder variant highlights the multifaceted cardiac manifestations of metabolic laminopathies.
Evidence of synergism among three genetic variants in a patient with LMNA-related lipodystrophy and amyotrophic lateral sclerosis leading to a remarkable nuclear phenotype.
Generation of an integration-free induced pluripotent stem cell line (PUMCHi001-A) from a patient with familial partial lipodystrophy type 2 (FPLD2) carrying a heterozygous p.R349W (c.1045C > T) mutation in the LMNA gene.
Premature cardiac death and aging is the hallmark of Hutchinson-Gilford syndrome a disease caused by defined mutations in the lamin A gene leading to a shortened prelamin A protein known as progerin. The here presented data suggest that Body-Mass-Index strongly correlates with progerin mRNA expression and inflammation. Progerin might contribute to well described accelerated biologic aging in obese individuals.
Non-R482 carriers present more frequently with arrhythmias than R482 carriers who twice as often have diabetes suggesting that follow-up for laminopathies could be adjusted for genotype. Non-R482 mutations require ultra-specialized cardiac follow-up and coronary artery disease should not be overlooked. Although overlapping phenotypes are found LMNA mutations essentially lead to tissue-specific diseases.
The LMNA-NTRK1 fusion was likely the molecular driver of tumorigenesis and metastasis in this patient and the observed effectiveness of crizotinib treatment provides clinical validation of this molecular target.
Several cardiac phenotypes were age-dependently increased in LMNA mutation carriers suggesting that ICD or CRT-D could suppress SCD after middle age; however LVD leading to end-stage heart failure was the only independent predictor for total mortality.
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.
Three heterozygous missense mutations were identified in unrelated patients - p. W520R (c.1558T > C) p.T528R (small es Cyrillic.1583capital ES Cyrillic > G) and p.R190P (c.569G > C). We consider these variants as pathogenic leading to isolated DCM with conduction defects or syndromic DCM forms with limb-girdle muscular dystrophy and Emery- Dreifuss muscular dystrophy.
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