Dataset Information

Cardiomyopathy in patients with POMT1-related congenital and limb-girdle muscular dystrophy.

ABSTRACT: Protein-o-mannosyl transferase 1 (POMT1) is a glycosyltransferase involved in ?-dystroglycan (?-DG) glycosylation. Clinical phenotype in POMT1-mutated patients ranges from congenital muscular dystrophy (CMD) with structural brain abnormalities, to limb-girdle muscular dystrophy (LGMD) with microcephaly and mental retardation, to mild LGMD. No cardiac involvement has until now been reported in POMT1-mutated patients. We report three patients who harbored compound heterozygous POMT1 mutations and showed left ventricular (LV) dilation and/or decrease in myocardial contractile force: two had a LGMD phenotype with a normal or close-to-normal cognitive profile and one had CMD with mental retardation and normal brain MRI. Reduced or absent ?-DG immunolabeling in muscle biopsies were identified in all three patients. Bioinformatic tools were used to study the potential effect of POMT1-detected mutations. All the detected POMT1 mutations were predicted in silico to interfere with protein folding and/or glycosyltransferase function. The report on the patients described here has widened the clinical spectrum associated with POMT1 mutations to include cardiomyopathy. The functional impact of known and novel POMT1 mutations was predicted with a bioinformatics approach, and results were compared with previous in vitro studies of protein-o-mannosylase function.

SUBMITTER: Bello L

PROVIDER: S-EPMC3499746 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Cardiomyopathy in patients with POMT1-related congenital and limb-girdle muscular dystrophy.

Bello Luca L Melacini Paola P Pezzani Raffaele R D'Amico Adele A Piva Luisa L Leonardi Emanuela E Torella Annalaura A Soraru Gianni G Palmieri Arianna A Smaniotto Gessica G Gavassini Bruno F BF Vianello Andrea A Nigro Vincenzo V Bertini Enrico E Angelini Corrado C Tosatto Silvio C E SC Pegoraro Elena E

European journal of human genetics : EJHG 20120502 12

Protein-o-mannosyl transferase 1 (POMT1) is a glycosyltransferase involved in α-dystroglycan (α-DG) glycosylation. Clinical phenotype in POMT1-mutated patients ranges from congenital muscular dystrophy (CMD) with structural brain abnormalities, to limb-girdle muscular dystrophy (LGMD) with microcephaly and mental retardation, to mild LGMD. No cardiac involvement has until now been reported in POMT1-mutated patients. We report three patients who harbored compound heterozygous POMT1 mutations and ...[more]

PMID: 22549409

Similar Datasets

Project description:BackgroundLimb-girdle muscular dystrophy R9 (LGMDR9) is a chronic progressive hereditary muscle disease, related to the Fukutin Related Protein (FKRP) gene, that may cause major disabilities, cardiomyopathy, and ventilatory failure. Knowledge of how LGMDR9 affects health-related quality of life (HRQoL) is relevant in treatment and care.ObjectiveTo investigate HRQoL in the Norwegian LGMDR9 population over 14 months and relation to fatigue and sleep quality.MethodsParticipants (16+ years) of the Norwegian LGMDR9 cohort study completed two HRQoL measures, i.e., Individualized Neuromuscular Quality of Life questionnaire (INQoL) and the 36-item Short Form (SF-36) at baseline, 8, and 14 months and measures of fatigue and sleep quality at 9 months.ResultsHRQoL response rate was 84/90 (75 c.826 C > A homozygotes and nine c.826 C > A compound heterozygotes). Compared to Norwegian normative data, all SF-36 domain scores were impaired (p≤0.006) except mental health in males (p = 0.05) and pain scores. During 14 months, perceived muscle weakness and the INQoL index (disease burden) worsened in c.826 C > A homozygotes. Compound heterozygotes reported more dysphagia and physical difficulties than homozygotes and showed a tendency towards worsening in weakness over time but some improvement on the INQoL index. Homozygous females reported generally poorer HRQoL and a higher burden than males. The INQoL index was related to perceived muscle weakness and fatigue, and fatigue to myalgia and mental distress. The prevalence of fatigue and poor sleep was 40% and 49%, respectively.ConclusionsThe 14-month follow-up period shows a worsening of perceived weakness and burden in c.826 C > A homozygotes, which can then be expected. The prevalence and impact of fatigue indicate a need for awareness and treatment of fatigue. Myalgia and mental distress are potential targets in the treatment of fatigue, which future studies need to establish. Sleep issues and gender-specific care needs also require attention in LGMDR9.

Project description:ObjectiveTo identify novel biomarkers as an alternative diagnostic tool for limb girdle muscular dystrophy (LGMD).BackgroundLGMD encompasses a group of muscular dystrophies characterized by proximal muscles weakness, elevated CK levels and dystrophic findings on muscle biopsy. Heterozygous CAPN3 mutations are associated with autosomal dominant LGMD-4, while biallelic mutations can cause autosomal recessive LGMD-1. Diagnosis is currently often based on invasive methods requiring muscle biopsy or blood tests. In most cases Western blotting (WB) analysis from muscle biopsy is essential for a diagnosis, as muscle samples are currently the only known tissues to express the full-length CAPN3 isoform.MethodsWe analyzed CAPN3 in a cohort including 60 LGMD patients. Selected patients underwent a complete neurological examination, electromyography, muscle biopsy, and skin biopsies for primary fibroblasts isolation. The amount of CAPN3 was evaluated by WB analysis in muscle and skin tissues. The total RNA isolated from muscle, fibroblast and urine was processed, and cDNA was used for qualitative analysis. The expression of CAPN3 was investigated by qRT-PCR. The CAPN3 3D structure has been visualized and analyzed using PyMOL.ResultsAmong our patients, seven different CAPN3 mutations were detected, of which two were novel. After sequencing CAPN3 transcripts from fibroblast and urine, we detected different CAPN3 isoforms surprisingly including the full-length transcript. We found comparable protein levels from fibroblasts and muscle tissue; in particular, patients harboring a novel CAPN3 mutation showed a 30% reduction in protein compared to controls from both tissues.ConclusionsOur findings showed for the first time the presence of the CAPN3 full-length transcript in urine and skin samples. Moreover, we demonstrated surprisingly comparable CAPN3 protein levels between muscle and skin samples, thus allowing us to hypothesize the use of skin biopsy and probably of urine samples as an alternative less invasive method to assess the amount of CAPN3 when molecular diagnosis turns out to be inconclusive.

Dataset Information

Cardiomyopathy in patients with POMT1-related congenital and limb-girdle muscular dystrophy.

Publications

Cardiomyopathy in patients with POMT1-related congenital and limb-girdle muscular dystrophy.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets