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Large genomic deletions: a novel cause of Ullrich congenital muscular dystrophy.

ABSTRACT: Two mutational mechanisms are known to underlie Ullrich congenital muscular dystrophy (UCMD): heterozygous dominant negatively-acting mutations and recessively-acting loss-of-function mutations. We describe large genomic deletions on chromosome 21q22.3 as a novel type of mutation underlying recessively inherited UCMD in 2 families. Clinically unaffected parents carrying large genomic deletions of COL6A1and COL6A2also provide conclusive evidence that haploinsufficiency for COL6A1and COL6A2is not a disease mechanism for Bethlem myopathy. Our findings have important implications for the genetic evaluation of patients with collagen VI-related myopathies as well as for potential therapeutic interventions for this patient population.

SUBMITTER: Foley AR

PROVIDER: S-EPMC5154621 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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Large genomic deletions: a novel cause of Ullrich congenital muscular dystrophy.

Foley A Reghan AR Hu Ying Y Zou Yaqun Y Yang Michele M Medne Līvija L Leach Meganne M Conlin Laura K LK Spinner Nancy N Shaikh Tamim H TH Falk Marni M Neumeyer Ann M AM Bliss Laurie L Tseng Brian S BS Winder Thomas L TL Bönnemann Carsten G CG

Annals of neurology 20110101 1

Two mutational mechanisms are known to underlie Ullrich congenital muscular dystrophy (UCMD): heterozygous dominant negatively-acting mutations and recessively-acting loss-of-function mutations. We describe large genomic deletions on chromosome 21q22.3 as a novel type of mutation underlying recessively inherited UCMD in 2 families. Clinically unaffected parents carrying large genomic deletions of COL6A1and COL6A2also provide conclusive evidence that haploinsufficiency for COL6A1and COL6A2is not ...[more]

PMID: 21280092

Similar Datasets

Comparative Genomic Hybridization: genomic control vs. Ullrich Congenital Muscular Dystrophy and Bethlem myopathy

Project description:Molecular characterization of collagen-VI related myopathies currently relies on standard sequencing, which yields a detection rate approximating 75-79% in Ullrich congenital muscular dystrophy (UCMD) and 60-65% in Bethlem myopathy (BM) patients as PCR-based techniques tend to miss gross genomic rearrangements as well as copy number variations (CNVs) in both the coding sequence and intronic regions. We have designed a custom oligonucleotide CGH array in order to investigate the presence of CNVs in the coding and non-coding regions of COL6A1, A2, A3, A5 and A6 genes and a group of genes functionally related to collagen VI. A cohort of 12 patients with UCMD/BM negative at sequencing analysis and 2 subjects carrying a single COL6 mutation whose clinical phenotype was not explicable by inheritance were selected and the occurrence of allelic and genetic heterogeneity explored. A deletion within intron 1A of the COL6A2 gene, occurring in compound heterozygosity with a small deletion in exon 28, previously detected by routine sequencing, was identified in a BM patient. RNA studies showed monoallelic transcription of the COL6A2 gene, thus elucidating the functional effect of the intronic deletion. No pathogenic mutations were identified in the remaining analyzed patients, either within COL6A genes, or in genes functionally related to collagen VI. Our custom CGH array may represent a useful complementary diagnostic tool, especially in recessive forms of the disease, when only one mutant allele is detected by standard sequencing. The intronic deletion we identified represents the first example of a pure intronic mutation in COL6A genes.

2010-01-28 | GSE20025 | GEO

Mutations in COL6A3 cause severe and mild phenotypes of Ullrich congenital muscular dystrophy.

Project description:Ullrich congenital muscular dystrophy (UCMD) is an autosomal recessive disorder characterized by generalized muscular weakness, contractures of multiple joints, and distal hyperextensibility. Homozygous and compound heterozygous mutations of COL6A2 on chromosome 21q22 have recently been shown to cause UCMD. We performed a genomewide screening with microsatellite markers in a consanguineous family with three sibs affected with UCMD. Linkage of the disease to chromosome 2q37 was found in this family and in two others. We analyzed COL6A3, which encodes the alpha3 chain of collagen VI, and identified one homozygous mutation per family. In family I, the three sibs carried an A-->G transition in the splice-donor site of intron 29 (6930+5A-->G), leading to the skipping of exon 29, a partial reduction of collagen VI in muscle biopsy, and an intermediate phenotype. In family II, the patient had an unusual mild phenotype, despite a nonsense mutation, R465X, in exon 5. Analysis of the patient's COL6A3 transcripts showed the presence of various mRNA species-one of which lacked several exons, including the exon containing the nonsense mutation. The deleted splice variant encodes collagen molecules that have a shorter N-terminal domain but that may assemble with other chains and retain a functional role. This could explain the mild phenotype of the patient who was still ambulant at age 18 years and who showed an unusual combination of hyperlaxity and finger contractures. In family III, the patient had a nonsense mutation, R2342X, causing absence of collagen VI in muscle and fibroblasts, and a severe phenotype, as has been described in patients with UCMD. Mutations in COL6A3 are described in UCMD for the first time and illustrate the wide spectrum of phenotypes which can be caused by collagen VI deficiency.

| S-EPMC419991 | biostudies-literature

Comparative Genomic Hybridization: genomic control vs. Ullrich Congenital Muscular Dystrophy and Bethlem myopathy

2010-01-27 | E-GEOD-20025 | biostudies-arrayexpress

Ullrich Congenital Muscular Dystrophy (UCMD): Clinical and Genetic Correlations.

Project description:OBJECTIVE:Ullrich congenital muscular dystrophy (UCMD) corresponds to the severe end of the clinical spectrum of neuromuscular disorders caused by mutations in the genes encoding collagen VI (COL VI). We studied four unrelated families with six affected children that had typical UCMD with dominant and recessive inheritance. MATERIALS & METHODS:Four unrelated Iranian families with six affected children with typical UCMD were analyzed for COLVI secretion in skin fibroblast culture and the secretion of COLVI in skin fibroblast culture using quantitative RT-PCR (Q-RT-PCR), and mutation identification was performed by sequencing of complementary DNA. RESULTS:COL VI secretion was altered in all studied fibroblast cultures. Two affected sibs carried a homozygous nonsense mutation in exon 12 of COL6A2, while another patient had a large heterozygous deletion in exon 5-8 of COL6A2. The two other affected sibs had homozygote mutation in exon 24 of COL6A2, and the last one was homozygote in COL6A1. CONCLUSION:In this study, we found out variability in clinical findings and genetic inheritance among UCMD patients, so that the patient with complete absence of COLVI was severely affected and had a large heterozygous deletion in COL6A2. In contrast, the patients with homozygous deletion had mild to moderate decrease in the secretion of COL VI and were mildly to moderately affected.

| S-EPMC3943075 | biostudies-literature

Tendon Extracellular Matrix Alterations in Ullrich Congenital Muscular Dystrophy.

Project description:Collagen VI (COLVI) is a non-fibrillar collagen expressed in skeletal muscle and most connective tissues. Mutations in COLVI genes cause two major clinical forms, Bethlem myopathy and Ullrich congenital muscular dystrophy (UCMD). In addition to congenital muscle weakness, patients affected by COLVI myopathies show axial and proximal joint contractures and distal joint hypermobility, which suggest the involvement of the tendon function. We examined a peroneal tendon biopsy and tenocyte culture of a 15-year-old patient affected by UCMD with compound heterozygous COL6A2 mutations. In patient's tendon biopsy, we found striking morphological alterations of tendon fibrils, consisting in irregular profiles and reduced mean diameter. The organization of the pericellular matrix of tenocytes, the primary site of collagen fibril assembly, was severely affected, as determined by immunoelectron microscopy, which showed an abnormal accumulation of COLVI and altered distribution of collagen I (COLI) and fibronectin (FBN). In patient's tenocyte culture, COLVI web formation and cell surface association were severely impaired; large aggregates of COLVI, which matched with COLI labeling, were frequently detected in the extracellular matrix. In addition, metalloproteinase MMP-2, an extracellular matrix-regulating enzyme, was increased in the conditioned medium of patient's tenocytes, as determined by gelatin zymography and western blot. Altogether, these data indicate that COLVI deficiency may influence the organization of UCMD tendon matrix, resulting in dysfunctional fibrillogenesis. The alterations of tendon matrix may contribute to the complex pathogenesis of COLVI related myopathies.

| S-EPMC4896961 | biostudies-literature

Pathogenic variants in COL6A3 cause Ullrich-like congenital muscular dystrophy in young Labrador Retriever dogs.

Project description:The collagen VI-related muscular dystrophies in people include a broad spectrum of diseases ranging from the severe Ullrich congenital muscular dystrophy to the mild Bethlem myopathy. Clinical features are attributable to both muscle and connective tissue and include progressive muscle weakness and respiratory failure, hyperlaxity of distal joints, and progressive contracture of large joints. Here we describe two different COL6A3 pathogenic variants in Labrador Retriever dogs that result in autosomal recessive or autosomal dominant congenital myopathies with hyperlaxity of distal joints and joint contracture, similar to the condition in people.

| S-EPMC7292757 | biostudies-literature

Cyclosporine A in Ullrich congenital muscular dystrophy: long-term results.

Project description:Six individuals with Ullrich congenital muscular dystrophy (UCMD) and mutations in the genes-encoding collagen VI, aging 5-9, received 3-5 mg/kg of cyclosporine A (CsA) daily for 1 to 3.2 years. The primary outcome measure was the muscle strength evaluated with a myometer and expressed as megalimbs. The megalimbs score showed significant improvement (P = 0.01) in 5 of the 6 patients. Motor function did not change. Respiratory function deteriorated in all. CsA treatment corrected mitochondrial dysfunction, increased muscle regeneration, and decreased the number of apoptotic nuclei. Results from this study demonstrate that long-term treatment with CsA ameliorates performance in the limbs, but not in the respiratory muscles of UCMD patients, and that it is well tolerated. These results suggest considering a trial of CsA or nonimmunosuppressive cyclosporins, that retains the PTP-desensitizing properties of CsA, as early as possible in UCMD patients when diaphragm is less compromised.

| S-EPMC3199070 | biostudies-literature

Ullrich Congenital Muscular Dystrophy Possibly Related With COL6A1 p.Gly302Arg Variant.

Project description:Ullrich congenital muscular dystrophy (UCMD) is characterized by congenital weakness, proximal joint contractures, and hyperlaxity of distal joints. UCMD is basically due to a defect in extra cellular matrix protein, collagen type VI. A 37-year-old woman who cannot walk independently visited our outpatient clinic. She had orthopedic deformities (scoliosis, joint contractures, and distal joint hyperlaxity), difficulty of respiration, and many skin keloids. Her hip computed tomography showed diffuse fatty infiltration and the 'central shadow' sign in thigh muscles. From the clinical information suggesting collagen type VI related muscle disorder, UCMD was highly considered. COL6A1 gene sequencing confirmed this patient as UCMD with novel c.904G>A (p.Gly302Arg) variant. If musculoskeletal and dermatologic manifestations and radiologic findings imply abnormalities in collagen type VI network, COL6A related congenital muscular dystrophy was to be suspected.

| S-EPMC4026620 | biostudies-literature

Novel COL6A3 frameshift variant in American Staffordshire Terrier dogs with Ullrich-like congenital muscular dystrophy.

Project description:Two (male and female) 10-month-old American Staffordshire Terrier littermates presented for progressive weakness, joint contracture, and distal limb joint hyperlaxity beginning around 6 months of age. Neurological examination, serum creatine kinase activity, infectious disease titers, cerebrospinal fluid analysis, and electrodiagnostic testing were performed. Muscle biopsies were collected for histopathology and immunofluorescence staining for localization of dystrophy associated proteins. Whole-genome sequencing (WGS) was performed on 1 affected dog. Variants were compared to a database of 671 unaffected dogs of multiple breeds. Histopathology confirmed a dystrophic phenotype and immunofluorescence staining of muscle cryosections revealed an absence of staining for collagen-6. WGS identified a homozygous 1 bp deletion in the COL6A3 gene, unique to the first affected dog. Sanger sequencing confirmed the homozygous presence of the frameshift variant in both affected dogs. This report describes the clinical features and most likely genetic basis of an Ullrich-like recessively inherited form of congenital muscular dystrophy in American Staffordshire Terriers.

| S-EPMC10658572 | biostudies-literature

The collagen VI-related myopathies Ullrich congenital muscular dystrophy and Bethlem myopathy.

Project description:Mutations in the genes COL6A1, COL6A2, and COL6A3, coding for three ? chains of collagen type VI, underlie a spectrum of myopathies, ranging from the severe congenital muscular dystrophy-type Ullrich (UCMD) to the milder Bethlem myopathy (BM), with disease manifestations of intermediate severity in between. UCMD is characterized by early-onset weakness, associated with pronounced distal joint hyperlaxity and the early onset or early progression of more proximal contractures. In the most severe cases ambulation is not achieved, or it may be achieved only for a limited period of time. BM may be of early or later onset, but is milder in its manifestations, typically allowing for ambulation well into adulthood, whereas typical joint contractures are frequently prominent. A genetic spectrum is emerging, with BM being caused mostly by dominantly acting mutations, although rarely recessive inheritance of BM is also possible, whereas both dominantly as well as recessively acting mutations underlie UCMD.

| S-EPMC5207779 | biostudies-literature

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