A form of muscular dystrophy associated with pathogenic variants in JAG2

Coppens, Sandra; Barnard, Alison M.; Puusepp, Sanna; Pajusalu, Sander; Õunap, Katrin; Vargas‐Franco, Dorianmarie; Bruels, Christine C.; Donkervoort, Sandra; Pais, Lynn; Chao, Katherine R.; Goodrich, Julia K.; England, Eleina; Weisburd, Ben; Gudmundsson, Sanna; O’Donnell-Luria, Anne; Nigul, Mait; Ilves, Pilvi; Mohassel, Payam; Siddique, Teepu; Milone, Margherita; Nicolau, Stefan; Maroofian, Reza; Houlden, Henry; Hanna, Michael G.; Quinlivan, R.; Toosi, Mehran Beiraghi; Karimiani, Ehsan Ghayoor; Costagliola, Sabine; Deconinck, Nicolas; Kadhim, Hazim; Macke, Erica L.; Lanpher, Brendan C.; Klee, Eric W.; Łusakowska, Anna; Kostera‐Pruszczyk, Anna; Hahn, Andreas; Schrank, Bertold; Nishino, Ichizo; Ogasawara, Masashi; Sherif, Rasha El; Stojkovic, Tanya; Nelson, Isabelle; Bonne, Gisèle; Cohen, Enzo; Boland‐Augé, Anne; Deleuze, Jean; Meng, Yao; Töpf, Ana; Vilain, Catheline; Pacak, Christina A.; Rivera‐Zengotita, Marie; Bönnemann, Carsten G.; Straub, Volker; Handford, Penny A.; Draper, Isabelle; Walter, Glenn A.; Kang, Peter B.

doi:10.1016/j.ajhg.2021.03.020

Cited by 23 publications

(12 citation statements)

References 69 publications

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“…Recently, pathogenic mutations in JAG2 ( JAGGED2 ) that are predicted to impair protein function have been identified in a cohort of patients. Their muscular dystrophy resembles EMARDD, including facial weakness, respiratory complications and mildly elevated CK level [ 61 ]. JAG2 encodes for a NOTCH3 ligand that contains several EGF repeats, similar to MEGF10 and other Notch ligands [ 62 ], and Notch3 is involved in satellite cell self-renewal in mouse [ 63 ].…”

Section: Gene Mutations That Cause Primary Satellite Cell-opathiesmentioning

confidence: 99%

“…In turn, disruption of Notch1 signalling in murine satellite cells phenocopies aspects of POGLUT1-deficiency, resulting in a dystrophic phenotype with reduction of Pax7-positive cells and decreased Pax7 expression, suggestive of defective self-renewal [ 187 ]. Thus LGMDR21 shares pathogenic features with EMARDD [ 55 , 57 , 58 ] and JAG2-myopathy [ 61 ], and can be considered a satellite cell-opathy.…”

Section: Genes That May Cause Novel Satellite Cell-opathiesmentioning

confidence: 99%

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Defining and identifying satellite cell-opathies within muscular dystrophies and myopathies

Ganassi

Muntoni

Zammit

2022

Experimental Cell Research

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Muscular dystrophies and congenital myopathies arise from specific genetic mutations causing skeletal muscle weakness that reduces quality of life. Muscle health relies on resident muscle stem cells called satellite cells, which enable life-course muscle growth, maintenance, repair and regeneration. Such tuned plasticity gradually diminishes in muscle diseases, suggesting compromised satellite cell function. A central issue however, is whether the pathogenic mutation perturbs satellite cell function directly and/or indirectly via an increasingly hostile microenvironment as disease progresses. Here, we explore the effects on satellite cell function of pathogenic mutations in genes (myopathogenes) that associate with muscle disorders, to evaluate clinical and muscle pathological hallmarks that define dysfunctional satellite cells. We deploy transcriptomic analysis and comparison between muscular dystrophies and myopathies to determine the contribution of satellite cell dysfunction using literature, expression dynamics of myopathogenes and their response to the satellite cell regulator PAX7. Our multimodal approach extends current pathological classifications to define Satellite Cell-opathies: muscle disorders in which satellite cell dysfunction contributes to pathology. Primary Satellite Cell-opathies are conditions where mutations in a myopathogene directly affect satellite cell function, such as in Progressive Congenital Myopathy with Scoliosis (MYOSCO) and Carey-Fineman-Ziter Syndrome (CFZS). Primary satellite cell-opathies are generally characterised as being congenital with general hypotonia, and specific involvement of respiratory, trunk and facial muscles, although serum CK levels are usually within the normal range. Secondary Satellite Cell-opathies have mutations in myopathogenes that affect both satellite cells and muscle fibres. Such classification aids diagnosis and predicting probable disease course, as well as informing on treatment and therapeutic development.

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Section: Gene Mutations That Cause Primary Satellite Cell-opathiesmentioning

confidence: 99%

Section: Genes That May Cause Novel Satellite Cell-opathiesmentioning

confidence: 99%

Defining and identifying satellite cell-opathies within muscular dystrophies and myopathies

Ganassi

Muntoni

Zammit

2022

Experimental Cell Research

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Section: Collaborationmentioning

confidence: 99%

“…In addition, Broad CMG analysts search for candidate genes across multiple projects for potential matches and connect the respective research groups. This collaborative approach has empowered numerous diagnoses and novel gene discoveries across the more than 10,000 families that we have studied to date (Coppens et al, 2021; Donkervoort et al, 2019; Mohassel et al, 2021). Due to joint calling, the allele count across the joint callset is displayed for all variants in the search results and aggregation of cases with common etiologies is easily enabled.…”

Section: Collaborationmentioning

confidence: 99%

seqr : A web‐based analysis and collaboration tool for rare disease genomics

et al. 2022

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Exome and genome sequencing have become the tools of choice for rare disease diagnosis, leading to large amounts of data available for analyses. To identify causal variants in these datasets, powerful filtering and decision support tools that can be efficiently used by clinicians and researchers are required. To address this need, we developed seqr — an open‐source, web‐based tool for family‐based monogenic disease analysis that allows researchers to work collaboratively to search and annotate genomic callsets. To date, seqr is being used in several research pipelines and one clinical diagnostic lab. In our own experience through the Broad Institute Center for Mendelian Genomics, seqr has enabled analyses of over 10,000 families, supporting the diagnosis of more than 3,800 individuals with rare disease and discovery of over 300 novel disease genes. Here, we describe a framework for genomic analysis in rare disease that leverages seqr's capabilities for variant filtration, annotation, and causal variant identification, as well as support for research collaboration and data sharing. The seqr platform is available as open source software, allowing low‐cost participation in rare disease research, and a community effort to support diagnosis and gene discovery in rare disease.

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“…Biallelic pathogenic variants in JAG2 were found in a cohort of 13 unrelated families with muscular dystrophy, with severity ranging from an early‐onset congenital muscular dystrophy (CMD) phenotype to a later‐onset LGMD phenotype 25 . Serum CK levels ranged from normal to four times the upper limit of normal.…”

Section: Introductionmentioning

confidence: 99%

The Notch signaling pathway in skeletal muscle health and disease

et al. 2022

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The Notch signaling pathway is a key regulator of skeletal muscle development and regeneration. Over the past decade, the discoveries of three new muscle disease genes have added a new dimension to the relationship between the Notch signaling pathway and skeletal muscle: MEGF10, POGLUT1, and JAG2. We review the clinical syndromes associated with pathogenic variants in each of these genes, known molecular and cellular functions of their protein products with a particular focus on the Notch signaling pathway, and potential novel therapeutic targets that may emerge from further investigations of these diseases. The phenotypes associated with two of these genes, POGLUT1 and JAG2, clearly fall within the realm of muscular dystrophy, whereas the third, MEGF10, is associated with a congenital myopathy/muscular dystrophy overlap syndrome classically known as early-onset myopathy, areflexia, respiratory distress, and dysphagia. JAG2 is a canonical Notch ligand, POGLUT1 glycosylates the extracellular domain of Notch receptors, and MEGF10 interacts with the intracellular domain of NOTCH1. Additional genes and their encoded proteins relevant to muscle function and disease with links to the Notch signaling pathway include TRIM32, ATP2A1 (SERCA1), JAG1, PAX7, and NOTCH2NLC. There is enormous potential to identify convergent mechanisms of skeletal muscle disease and new therapeutic targets through further investigations of the Notch signaling pathway in the context of skeletal muscle development, maintenance, and disease.

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A form of muscular dystrophy associated with pathogenic variants in JAG2

Cited by 23 publications

References 69 publications

Defining and identifying satellite cell-opathies within muscular dystrophies and myopathies

Defining and identifying satellite cell-opathies within muscular dystrophies and myopathies

seqr : A web‐based analysis and collaboration tool for rare disease genomics

The Notch signaling pathway in skeletal muscle health and disease

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