Frequency and characterisation of anoctamin 5 mutations in a cohort of Italian limb-girdle muscular dystrophy patients

Magri, Francesca; Bo, Roberto Del; D’Angelo, Maria Grazia; Sciacco, Monica; Gandossini, S.; Govoni, Alessandra; Napoli, Laura; Ciscato, Patrizia; Fortunato, Francesco; Brighina, Erika; Bonato, Sara; Bordoni, Andreina; Lucchini, Valeria; Corti, Stefania; Moggio, Maurizio; Bresolin, Nereo; Comi, Giacomo P.

doi:10.1016/j.nmd.2012.05.001

Cited by 56 publications

(58 citation statements)

References 20 publications

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“…Focusing on LGMD cases, for example, the number of patients with dysferlinopathy or calpainopathy, accounting for more than 40% of LGMDs in Italy, 19,20 is small because of extensive studies previously performed on these genes. As previously mentioned, samples from more than 90% of our patients had already been tested by Sanger sequencing or other laboratory techniques.…”

Section: Methodsmentioning

confidence: 99%

The genetic basis of undiagnosed muscular dystrophies and myopathies

Savarese

Fruscio²,

Torella³

et al. 2016

Neurology

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Objective: To apply next-generation sequencing (NGS) for the investigation of the genetic basis of undiagnosed muscular dystrophies and myopathies in a very large cohort of patients. Methods: We applied an NGS-based platform namedMotorPlex to our diagnostic workflow to test muscle disease genes with a high sensitivity and specificity for small DNA variants. We analyzed 504 undiagnosed patients mostly referred as being affected by limb-girdle muscular dystrophy or congenital myopathy. Results: MotorPlex provided a complete molecular diagnosis in 218 cases (43.3%). A further 160 patients (31.7%) showed as yet unproven candidate variants. Pathogenic variants were found in 47 of 93 genes, and in more than 30%of cases, the phenotype was nonconventional, broadening the spectrum of disease presentation in at least 10 genes. Conclusions: Our large DNA study of patients with undiagnosed myopathy is an example of the ongoing revolution in molecular diagnostics, highlighting the advantages in using NGS as a first-tier approach for heterogeneous genetic conditions

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Section: Methodsmentioning

confidence: 99%

The genetic basis of undiagnosed muscular dystrophies and myopathies

Savarese

Fruscio²,

Torella³

et al. 2016

Neurology

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“…However, we could not detect any difference in membrane localization between patient and control samples (Supplemental Figure 7). Membrane discontinuities were observed in the muscle biopsy of the grandfather (PTI-1), a feature that is typical of dysferlinopathies and related muscle disorders (20,21). We established association of DYSF with POPDC1 by colocalization and coimmunoprecipitation (Supplemental Figure 8).…”

Section: Popdc1 Is a Disease-causing Gene Associated With Cardiac Dismentioning

confidence: 94%

POPDC1S201F causes muscular dystrophy and arrhythmia by affecting protein trafficking

Schindler

Scotton

Zhang

et al. 2015

Journal of Clinical Investigation

292

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The Popeye domain-containing 1 (POPDC1) gene encodes a plasma membrane-localized cAMP-binding protein that is abundantly expressed in striated muscle. In animal models, POPDC1 is an essential regulator of structure and function of cardiac and skeletal muscle; however, POPDC1 mutations have not been associated with human cardiac and muscular diseases. Here, we have described a homozygous missense variant (c.602C>T, p.S201F) in POPDC1, identified by whole-exome sequencing, in a family of 4 with cardiac arrhythmia and limb-girdle muscular dystrophy (LGMD). This allele was absent in known databases and segregated with the pathological phenotype in this family. We did not find the allele in a further screen of 104 patients with a similar phenotype, suggesting this mutation to be family specific. Compared with WT protein, POPDC1S201F displayed a 50% reduction in cAMP affinity, and in skeletal muscle from patients, both POPDC1S201F and WT POPDC2 displayed impaired membrane trafficking. Forced expression of POPDC1S201F in a murine cardiac muscle cell line (HL-1) increased hyperpolarization and upstroke velocity of the action potential. In zebrafish, expression of the homologous mutation (popdc1S191F) caused heart and skeletal muscle phenotypes that resembled those observed in patients. Our study therefore identifies POPDC1 as a disease gene causing a very rare autosomal recessive cardiac arrhythmia and LGMD, expanding the genetic causes of this heterogeneous group of inherited rare diseases

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“…Limb girdle muscular dystrophy type 2L (LGMD2L) is a condition characterized by proximal weakness affecting primarily the pelvic girdle and leg muscles, with less prominent distal leg weakness and high CK values [Hicks et al, 2011]. LGMD2L, together with a more distal variant also known as nondysferlin Miyoshi muscular dystrophy type 3 (MMD3) as well as some cases of isolated hyperCKaemia and pseudometabolic myopathy, have been shown to be associated with recessive mutations in the ANO5 gene [MIM #608662; Bolduc et al, 2010;Bouquet et al, 2012;Deschauer et al, 2011;Hicks et al, 2011;Magri et al, 2012;Milone et al, 2012;Little et al, 2013;Neusch et al, 2012;Penttilä et al, 2012;Pénisson-Besnier et al, 2012;Schessl et al, 2012;Wahbi et al, 2012;Witting et al, 2012]. The prevalence of ANO5 gene related conditions, or so-called anoctaminopathies, is not yet fully established, but preliminary data from Northern England indicate that LGMD2L is the 3rd most common type of LGMD with a minimum prevalence of 0.27/100 000 [Hicks et al, 2011].…”

Section: Introductionmentioning

confidence: 99%

ANO5Gene Analysis in a Large Cohort of Patients with Anoctaminopathy: Confirmation of Male Prevalence and High Occurrence of the Common Exon 5 Gene Mutation

et al. 2013

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Limb girdle muscular dystrophy type 2L or anoctaminopathy is a condition mainly characterized by adult onset proximal lower limb muscular weakness and raised CK values, due to recessive ANO5 gene mutations. An exon 5 founder mutation (c.191dupA) has been identified in most of the British and German LGMD2L patients so far reported. We aimed to further investigate the prevalence and spectrum of ANO5 gene mutations and related clinical phenotypes, by screening 205 undiagnosed patients referred to our molecular service with a clinical suspicion of anoctaminopathy. A total of 42 unrelated patients had two ANO5 mutations (21%), whereas 14 carried a single change. We identified 34 pathogenic changes, 15 of which are novel. The c.191dupA mutation represents 61% of mutated alleles and appears to be less prevalent in non-Northern European populations. Retrospective clinical analysis corroborates the prevalently proximal lower limb phenotype, the male predominance and absence of major cardiac or respiratory involvement. Identification of cases with isolated hyperCKaemia and very late symptomatic male and female subjects confirms the extension of the phenotypic spectrum of the disease. Anoctaminopathy appears to be one of the most common adult muscular dystrophies in Northern Europe, with a prevalence of about 20%-25% in unselected undiagnosed cases.

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Frequency and characterisation of anoctamin 5 mutations in a cohort of Italian limb-girdle muscular dystrophy patients

Cited by 56 publications

References 20 publications

The genetic basis of undiagnosed muscular dystrophies and myopathies

The genetic basis of undiagnosed muscular dystrophies and myopathies

POPDC1S201F causes muscular dystrophy and arrhythmia by affecting protein trafficking

ANO5Gene Analysis in a Large Cohort of Patients with Anoctaminopathy: Confirmation of Male Prevalence and High Occurrence of the Common Exon 5 Gene Mutation

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