Expression of the Z Variant of α1-Antitrypsin Suppresses Hepatic Cholesterol Biosynthesis in Transgenic Zebrafish.

Individuals homozygous for the Pi*Z allele of SERPINA1 (ZAAT) are susceptible to lung disease due to insufficient α1-antitrypsin secretion into the circulation and may develop liver disease due to compromised protein folding that leads to inclusion body formation in the endoplasmic reticulum (ER) of hepatocytes. Transgenic zebrafish expressing human ZAAT show no signs of hepatic accumulation despite displaying serum insufficiency, suggesting the defect in ZAAT secretion occurs independently of its tendency to form inclusion bodies. In this study, proteomic, transcriptomic, and biochemical analysis provided evidence of suppressed Srebp2-mediated cholesterol biosynthesis in the liver of ZAAT-expressing zebrafish.

X-linked Recessive Distal Myopathy With Hypertrophic Cardiomyopathy Caused by a Novel Mutation in the FHL1 Gene.

FHL1 gene mutations are associated with reducing body myopathy, X-linked myopathy with postural muscle atrophy, scapuloperoneal myopathy, Emery-Dreifuss muscular dystrophy, and isolated hypertrophic cardiomyopathy. We describe a boy with a family history consistent with X-linked distal myopathy/cardiomyopathy. The boy first presented at age 14 years and was found to have distal wasting and weakness.

FHL1 mutants that cause clinically distinct human myopathies form protein aggregates and impair myoblast differentiation.

FHL1 mutations cause several clinically heterogeneous myopathies, including reducing body myopathy (RBM), scapuloperoneal myopathy (SPM) and X-linked myopathy with postural muscle atrophy (XMPMA). The molecular mechanisms underlying the pathogenesis of FHL1 myopathies are unknown. Protein aggregates, designated 'reducing bodies', that contain mutant FHL1 are detected in RBM muscle but not in several other FHL1 myopathies.

Evidence for FHL1 as a novel disease gene for isolated hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is characterized by asymmetric left ventricular hypertrophy, diastolic dysfunction and myocardial disarray. HCM is caused by mutations in sarcomeric genes, but in >40% of patients, the mutation is not yet identified. We hypothesized that FHL1, encoding four-and-a-half-LIM domains 1, could be another disease gene since it has been shown to cause distinct myopathies, sometimes associated with cardiomyopathy.

Four and a half LIM protein 1 gene mutations cause four distinct human myopathies: a comprehensive review of the clinical, histological and pathological features.

Mutations in the four and a half LIM protein 1 (FHL1) gene were recently identified as the cause of four distinct skeletal muscle diseases. Since the initial report outlining the first fhl1 mutation in 2008, over 25 different mutations have been identified in patients with reducing body myopathy, X-linked myopathy characterized by postural muscle atrophy, scapuloperoneal myopathy and Emery-Dreifuss muscular dystrophy. Reducing body myopathy was first described four decades ago, its underlying genetic cause was unknown until the discovery of fhl1 mutations.

SLIMMER (FHL1B/KyoT3) interacts with the proapoptotic protein Siva-1 (CD27BP) and delays skeletal myoblast apoptosis.

The fhl1 gene encoding four-and-a-half LIM protein-1 (FHL1) and its spliced isoform, SLIMMER, is mutated in reducing body myopathy, X-linked myopathy with postural muscle atrophy, scapuloperoneal myopathy, and rigid spine syndrome. In this study we have identified a novel function for SLIMMER in delaying skeletal muscle apoptosis via an interaction with the proapoptotic protein Siva-1. Siva-1 was identified as a SLIMMER-specific-interacting protein using yeast two-hybrid screening, direct-binding studies, and glutathione S-transferase pulldown analysis of murine skeletal muscle lysates.