Ovarian failure and dilated cardiomyopathy due to a novel lamin mutation

Abstract

Two unrelated young women presented with similar dysmorphic features including severe retrognathia, beaked nose, narrow chest, sloping shoulders, and an acrogeric appearance of the hands and feet. Neither had any evidence of skeletal myopathy, but both developed progressive dilated cardiomyopathy, both experienced premature ovarian failure, and both were found to have the same heterozygous novel missense mutation c.176T>G in exon 1 of the LMNA gene, resulting in a leucine to arginine change at codon 59 (Leu59Arg). Mutations in the LMNA gene cause a variety of disorders including dilated cardiomyopathy, muscular dystrophy, familial lipodystrophy, progeria, atypical progeroid syndromes, and mandibuloacral dysplasia. Genotype-phenotype correlation has been reported for some of these conditions. Our patients are the only ones known to have the specific mutation Leu59Arg and also share a set of features not entirely consistent with any of the laminopathies previously described. A previously reported patient with an adjacent mutation (Ala57Pro) had "atypical Werner syndrome" with dilated cardiomyopathy, hypogonadism, and sloping shoulders. While each of these clinical features does occur in other laminopathy syndromes, these patients form a phenotypic cluster distinct from other laminopathies and clinically overlapping with Malouf syndrome. LMNA sequencing should be considered for patients presenting with dilated cardiomyopathy and hypergonadotropic hypogonadism, including those previously diagnosed with Malouf syndrome.

Case Report of Malouf Syndrome not Associated with LMNA Gene Mutation

“…Mutations in the LMNA gene cause a variety of disorders including dilated cardiomyopathy, muscular dystrophy, familial lipodystrophy, progeria, atypical progeroid syndromes, and mandibuloacral dysplasia. Phenotypic features in the present case are very similar to 3 cases reported by McPherson et al, 3 Nguyen et al,…”

Concordance of gene expression in human protein complexes reveals tissue specificity and pathology

“…The LMNA gene (and protein complex) provided an example associated both with different phenotypes and a large variety of affected tissues (22), such as dilated cardiomyopathy (19,23), Charcot-Marie-Tooth disease (20), muscular dystrophy(21) or Hutchinson-Gilford progeria syndrome (24) (for details please refer to Supplementary Text S1). These LMNA- associated diseases have in common that they all show a high diversity of affected tissues (mainly heart, muscle and skin) and distinct phenotypes.…”

Lamin A/C mutations in dilated cardiomyopathy

“…Lamin A and C distribution were affected in these cells and were either present in a honeycomb pattern [21] or distributed unevenly along the inner nuclear lamina [22]. Some fibroblasts had lamin A and C aggregates close to the lamina which did not interact with emerin, DNA or RNA [23].…”