Mutations in Alström protein impair terminal differentiation of cardiomyocytes

Shenje, Lincoln T.; Andersen, Peter; Halushka, Marc K.; Lui, Cecillia; Fernandez, Laviel; Collin, Gayle B.; Amat-Alarcon, Nuria; Meschino, Wendy S.; Cutz, Ernest; Chang, Kenneth; Yonescu, Raluca; Batista, Denise; Chen, Yan; Chelko, Stephen P.; Crosson, Jane E.; Scheel, Janet; Vricella, Luca A.; Craig, Brian; Marosy, Beth; Mohr, David; Hetrick, Kurt N.; Romm, Jane; Scott, Alan F.; Valle, David; Naggert, Jürgen Κ.; Kwon, Chulan; Doheny, Kimberly F.; Judge, Daniel P.

doi:10.1038/ncomms4416

Cited by 71 publications

(96 citation statements)

References 48 publications

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“…Dilated mitogenic cardiomyopathy (MCM) occurs in approximately 70% of patients peri-natally 3,4 , and ALMS1 mutations are a significant cause of idiopathic MCM 5 . In addition, restrictive cardiomyopathy with fibrosis and pulmonary hypertension can develop during adolescence or adulthood 3,4 .…”

Section: Introductionmentioning

confidence: 99%

The phenotypic and molecular genetic spectrum of Alström syndrome in 44 Turkish kindreds and a literature review of Alström syndrome in Turkey

et al. 2014

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Alström Syndrome is an autosomal recessive disease characterized by multiple organ involvement, including neurosensory vision and hearing loss, childhood obesity, diabetes mellitus, cardiomyopathy, hypogonadism, and pulmonary, hepatic, renal failure, and systemic fibrosis. Alström Syndrome is caused by mutations in ALMS1, and ALMS1 protein is thought to play a role in microtubule organization, intraflagellar transport, endosome recycling and cell cycle regulation. Here, we report extensive phenotypic and genetic analysis of a large cohort of Turkish patients with Alström Syndrome. We evaluated 61 Turkish patients, including 11 previously reported, for both clinical spectrum and mutations in ALMS1. To reveal the molecular diagnosis of the patients, there different approaches were used in combination, a cohort of patients were screened by the gene array to detect the common mutations in ALMS1 gene, then in patients having any of common ALMS1 mutations were subjected to direct DNA sequencing or next generation sequencing for the screening of mutations in all coding regions of the gene. In total, 20 distinct disease-causing nucleotide changes in ALMS1 have been identified, 8 of which are novel, thereby increasing the reported ALMS1 mutations by 6% (8/120). Five disease-causing variants were identified in more than one kindred, but most alleles were unique to each single patient and identified only once (16/20). So far, 16 mutations identified were specific to the Turkish population, and four have also been reported in other ethnicities. Additionally, 49 variants of uncertain pathogenicity were noted, and four of these were very rare and probably or likely deleterious according to in silico mutation prediction analyses. Alström Syndrome has a relatively high incidence in Turkey and the present study shows that the ALMS1 mutations are largely heterogeneous; thus, these data from a particular population may provide a unique source for the identification of additional mutations underlying Alström Syndrome and contribute to genotype-phenotype correlation studies.

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Section: Introductionmentioning

confidence: 99%

The phenotypic and molecular genetic spectrum of Alström syndrome in 44 Turkish kindreds and a literature review of Alström syndrome in Turkey

et al. 2014

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“…Beyond optimization of the patient’s care, recognition of recessive inheritance as the underlying mechanism for sporadic disease, conferring a 25% recurrence risk, has informed family planning. Insights into the pathobiology of mitogenic cardiomyopathy, a form of DCM in Alström syndrome characterized by myocyte nuclear hypertrophy and marked mitotic activity, are emerging [Chang et al, 2010, Shenje et al, 2014, Louw et al, 2014], but further research will be required to develop individualized, mechanism-based therapy beyond traditional reverse cardiac remodeling drugs.…”

Section: Discussionmentioning

confidence: 99%

Exome sequencing establishes diagnosis of Alström syndrome in an infant presenting with non‐syndromic dilated cardiomyopathy

Long

Evans

Olson

2015

American J of Med Genetics Pt A

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Idiopathic dilated cardiomyopathy is a heritable, genetically heterogeneous disorder characterized by progressive heart failure. Dilated cardiomyopathy typically exhibits autosomal dominant inheritance, yet frequently remains clinically silent until adulthood. We sought to discover the molecular basis of idiopathic, non-syndromic dilated cardiomyopathy in a one-month-old male presenting with severe heart failure. Previous comprehensive testing of blood, urine, and skin biopsy specimen was negative for metabolic, mitochondrial, storage, and infectious etiologies. Ophthalmologic examination was normal. Chromosomal microarray and commercial dilated cardiomyopathy gene panel testing failed to identify a causative mutation. Parental screening echocardiograms revealed no evidence of clinically silent dilated cardiomyopathy. Whole exome sequencing was carried out on the family trio on a research basis, filtering for rare, deleterious, recessive and de novo genetic variants. Pathogenic compound heterozygous truncating mutations were identified in ALMS1, diagnostic of Alström syndrome and prompting disclosure of genetic findings. Alström syndrome is a known cause for dilated cardiomyopathy in children yet delayed and mis-diagnosis are common owing to its rarity and age-dependent emergence of multisystem clinical manifestations. At six months of age the patient ultimately developed bilateral nystagmus and hyperopia, features characteristic of the syndrome. Early diagnosis is guiding clinical monitoring of other organ systems and allowing for presymptomatic intervention. Furthermore, recognition of recessive inheritance as the mechanism for sporadic disease has informed family planning. This case highlights a limitation of standard gene testing panels for pediatric dilated cardiomyopathy and exemplifies the potential for whole exome sequencing to solve a diagnostic dilemma and enable personalized care.

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“…Further studies need to be done to determine if quiescent cardiomyocytes can be brought back into cell cycle through this approach. In a study involving human patients with persistent postnatal cardiomyocyte replication Shenje et al [40] identified mutation in ALMS1 leading to deficiency of Alstrom protein and as a result impairing postnatal cardiomyocyte cell cycle arrest. The belief that postnatal cardiomyocytes are quiescent is challenged by a recent study by Naqvi et al [41] which identifies a one-time proliferative burst of cardiomyocyte at a small preadolescence window resulting in an increase in cardiomyocyte number by approximately 40%.…”

Section: Discussion and Future Directionsmentioning

confidence: 99%

MicroRNAs Inducing Proliferation of Quiescent Adult Cardiomyocytes

Pandey

Ahmed

2015

Cardiovasc Regen Med

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In the United States, each year over 700,000 people suffer from a heart attack and over 25% of deaths are related to heart disease, making it the leading cause of death. Following ischemic injury a part of the heart muscle is replaced by a scar tissue, reducing its functioning capacity. Recent advancements in surgical intervention and pharmacotherapy only provide symptomatic relief and do not address the root cause of the problem which is the massive loss of cardiomyocytes (CM). Therefore, the development of novel therapeutic intervention for the repair and regeneration of ischemic myocardium remains an area of intense research. While existing CM in zebra fish and neonatal mice are known to proliferate and replenish the infarcted heart, it has been shown that adult mammalian CM lose this ability, thus preventing regeneration of the scar tissue. There have been many attempts to facilitate regeneration of ischemic heart but have met with limited success. Micro-RNAs (miRNAs) are one of the promising candidates towards this goal as they are known to play important regulatory roles during differentiation and tissue regeneration, and regulate genetic information by post-transcriptional modification as well as regulation of other miRNAs. While previous work by Eulalio et al., showed miRNAs inducing proliferation in neonatal CM (NCM), we here identify miRNAs inducing proliferation of rat adult-CM (ACM). This commentary while analyses recent work by Eulalio et al [1] also shows some new data with microRNAs in rat adult-CMs. Further work into the mechanism of these miRNAs can determine their therapeutic potential towards regenerating cardiac tissue post ischemic injury.

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Mutations in Alström protein impair terminal differentiation of cardiomyocytes

Cited by 71 publications

References 48 publications

The phenotypic and molecular genetic spectrum of Alström syndrome in 44 Turkish kindreds and a literature review of Alström syndrome in Turkey

The phenotypic and molecular genetic spectrum of Alström syndrome in 44 Turkish kindreds and a literature review of Alström syndrome in Turkey

Exome sequencing establishes diagnosis of Alström syndrome in an infant presenting with non‐syndromic dilated cardiomyopathy

MicroRNAs Inducing Proliferation of Quiescent Adult Cardiomyocytes

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