title: 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.
authors.affiliation: Department of Medical Genetics, Marshfield Clinic, Marshfield, Wisconsin 54449, USA. mcpherson.elizabeth@marshfieldclinic.org
authors.forename: Elizabeth
authors.initials: E
authors.lastname: McPherson
authors.forename: Lesley
authors.initials: L
authors.lastname: Turner
authors.forename: Ivan
authors.initials: I
authors.lastname: Zador
authors.forename: Kara
authors.initials: K
authors.lastname: Reynolds
authors.forename: David
authors.initials: D
authors.lastname: Macgregor
authors.forename: Philip F
authors.initials: PF
authors.lastname: Giampietro
mesh_terms: D000293:Adolescent; D019943:Amino Acid Substitution; D002311:Cardiomyopathy, Dilated / Q000235:genetics*; D005260:Female; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D034904:Lamin Type A / Q000235:genetics*; D008060:Lipodystrophy / Q000235:genetics*; D020125:Mutation, Missense; D010641:Phenotype; D016649:Primary Ovarian Insufficiency / Q000235:genetics*; D013577:Syndrome; D014898:Werner Syndrome / Q000235:genetics
chemical_list: C494847:LMNA protein, human; D034904:Lamin Type A