FHL1

Abstract: Emery-Dreifuss muscular dystrophy (EDMD) is a rare disorder characterized by early joint contractures, muscular dystrophy, and cardiac involvement with conduction defects and arrhythmias So far, only 35% of EDMD cases are genetically elucidated and associated with EMD or LMNA gene mutations, suggesting the existence of additional major genes By whole-genome scan, we identified linkage to the Xq263 locus containing the FHL1 gene in three informative families belonging to our EMD- and LMNA-negative cohort Analysis of the FHL1 gene identified seven mutations, in the distal exons of FHL1 in these families, three additional families, and one isolated case, which differently affect the three FHL1 protein isoforms: two missense mutations affecting highly conserved cysteines, one abolishing the termination codon, and four out-of-frame insertions or deletions The predominant phenotype was characterized by myopathy with scapulo-peroneal and/or axial distribution, as well as joint contractures, and associated with a peculiar cardiac disease characterized by conduction defects, arrhythmias, and hypertrophic cardiomyopathy in all index cases of the seven families Heterozygous female carriers were either asymptomatic or had cardiac disease and/or mild myopathy Interestingly, four of the FHL1-mutated male relatives had isolated cardiac disease, and an overt hypertrophic cardiomyopathy was present in two Expression and functional studies demonstrated that the FHL1 proteins were severely reduced in all tested patients and that this was associated with a severe delay in myotube formation in the two patients for whom myoblasts were available In conclusion, FHL1 should be considered as a gene associated with the X-linked EDMD phenotype, as well as with hypertrophic cardiomyopathy

Abstract: Scapuloperoneal (SP) syndrome encompasses heterogeneous neuromuscular disorders characterized by weakness in the shoulder-girdle and peroneal muscles. In a large Italian-American pedigree with dominant SP myopathy (SPM) previously linked to chromosome 12q, we have mapped the disease to Xq26, and, in all of the affected individuals, we identified a missense change (c.365G→C) in the FHL1 gene encoding four-and-a-half-LIM protein 1 (FHL1). The mutation substitutes a serine for a conserved trypophan at amino acid 122 in the second LIM domain of the protein. Western blot analyses of muscle extracts revealed FHL1 loss that paralleled disease severity. FHL1 and an isoform, FHL1C, are highly expressed in skeletal muscle and may contribute to stability of sarcomeres and sarcolemma, myofibrillary assembly, and transcriptional regulation. This is the first report, to our knowledge, of X-linked dominant SP myopathy and the first human mutation in FHL1.

Abstract: Four and a half LIM domain protein 1 (FHL1) is the founding member of the FHL family of proteins characterized by the presence of four and a half highly conserved LIM domains. The LIM domain is a protein-interaction motif and is involved in linking proteins with both the actin cytoskeleton and transcriptional machinery. To date, more than 25 different protein interactions have been identified for full length FHL1 and its spliced variants, and these interactions can be mapped to a variety of functional classes. Because FHL1 is expressed predominantly in skeletal muscle, all of these proteins interactions translate into a multifunctional and integral role for FHL1 in muscle development, structural maintenance, and signalling. Importantly, 27 FHL1 genetic mutations have been identified that result in at least six different X-linked myopathies, with patients often presenting with cardiovascular disease. FHL1 expression is also significantly up-regulated in a variety of cardiac disorders, even at the earliest stages of disease onset. Alternatively, FHL1 expression is suppressed in a variety of cancers, and ectopic FHL1 expression offers potential for some phenotype rescue. This review focuses on recent studies of FHL1 in muscular dystrophies and cardiovascular disease, and provides a comprehensive review of FHL1s multifunctional roles in skeletal muscle.