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1.  Missense mutations in β-1,3-N-acetylglucosaminyltransferase 1 (B3GNT1) cause Walker–Warburg syndrome 
Human Molecular Genetics  2013;22(9):1746-1754.
Several known or putative glycosyltransferases are required for the synthesis of laminin-binding glycans on alpha-dystroglycan (αDG), including POMT1, POMT2, POMGnT1, LARGE, Fukutin, FKRP, ISPD and GTDC2. Mutations in these glycosyltransferase genes result in defective αDG glycosylation and reduced ligand binding by αDG causing a clinically heterogeneous group of congenital muscular dystrophies, commonly referred to as dystroglycanopathies. The most severe clinical form, Walker–Warburg syndrome (WWS), is characterized by congenital muscular dystrophy and severe neurological and ophthalmological defects. Here, we report two homozygous missense mutations in the β-1,3-N-acetylglucosaminyltransferase 1 (B3GNT1) gene in a family affected with WWS. Functional studies confirmed the pathogenicity of the mutations. First, expression of wild-type but not mutant B3GNT1 in human prostate cancer (PC3) cells led to increased levels of αDG glycosylation. Second, morpholino knockdown of the zebrafish b3gnt1 orthologue caused characteristic muscular defects and reduced αDG glycosylation. These functional studies identify an important role of B3GNT1 in the synthesis of the uncharacterized laminin-binding glycan of αDG and implicate B3GNT1 as a novel causative gene for WWS.
PMCID: PMC3613162  PMID: 23359570
2.  Genomic Organisation, Embryonic Expression and Biochemical Interactions of the Zebrafish Junctional Adhesion Molecule Family of Receptors 
PLoS ONE  2012;7(7):e40810.
The mammalian JAM family is composed of three cell surface receptors. Interactions between the proteins have well-characterised roles in inflammation and tight junction formation, but little is known about their function in early development. Recently, we identified a role for jamb and jamc in zebrafish myocyte fusion. Genome duplication in the teleost lineage raised the possibility that additional JAM family paralogues may also function in muscle development. To address this, we searched the zebrafish genome to identify potential paralogues and confirmed their homology, bringing the total number of zebrafish jam family members to six. We then compared the physical binding properties of each paralogue by surface plasmon resonance and determined the gene expression patterns of all zebrafish jam genes at different stages of development. Our results suggest a significant sub-functionalisation of JAM-B and JAM-C orthologues with respect to binding strength (but not specificity) and gene expression. The paralogous genes, jamb2 and jamc2, were not detected in the somites or myotome of wild-type embryos. We conclude that it is unlikely that the paralogues have a function in primary myogenesis.
PMCID: PMC3399880  PMID: 22815827
3.  Jamb and Jamc Are Essential for Vertebrate Myocyte Fusion 
PLoS Biology  2011;9(12):e1001216.
Jamb and Jamc are an essential cell surface receptor pair that interact to drive fusion between muscle precursor cells during zebrafish development.
Cellular fusion is required in the development of several tissues, including skeletal muscle. In vertebrates, this process is poorly understood and lacks an in vivo-validated cell surface heterophilic receptor pair that is necessary for fusion. Identification of essential cell surface interactions between fusing cells is an important step in elucidating the molecular mechanism of cellular fusion. We show here that the zebrafish orthologues of JAM-B and JAM-C receptors are essential for fusion of myocyte precursors to form syncytial muscle fibres. Both jamb and jamc are dynamically co-expressed in developing muscles and encode receptors that physically interact. Heritable mutations in either gene prevent myocyte fusion in vivo, resulting in an overabundance of mononuclear, but otherwise overtly normal, functional fast-twitch muscle fibres. Transplantation experiments show that the Jamb and Jamc receptors must interact between neighbouring cells (in trans) for fusion to occur. We also show that jamc is ectopically expressed in prdm1a mutant slow muscle precursors, which inappropriately fuse with other myocytes, suggesting that control of myocyte fusion through regulation of jamc expression has important implications for the growth and patterning of muscles. Our discovery of a receptor-ligand pair critical for fusion in vivo has important implications for understanding the molecular mechanisms responsible for myocyte fusion and its regulation in vertebrate myogenesis.
Author Summary
The fusion of precursor cells is a crucial step in many biological processes, one of which is the development of skeletal muscle. The molecular and cell biology of fusion of muscle precursors has been well described in Drosophila melanogaster larvae, leading to insights into the process in vertebrates. However, the identity and mechanism of action of essential cell surface proteins for fusion between vertebrate muscle precursors has previously been lacking. Here, we describe a vertebrate-specific cell surface receptor pair that is essential for fusion in zebrafish: Jamb and Jamc. Loss of function of either receptor causes a near-complete block in fusion, resulting in an overabundance of mononucleate muscle fibres that are otherwise overtly normal. We demonstrate that Jamb and Jamc physically interact and are co-expressed by muscle precursors. Moreover, we show that the interaction between them is essential for fusion between neighbouring precursors in an embryo. We hypothesise that binding of Jamb to Jamc is a necessary recognition and adhesion step permissive for, but not sufficient to cause, myocyte fusion. Knowledge of these molecular components in vertebrates will lead to better understanding of how fusion is controlled to pattern skeletal muscle tissue.
PMCID: PMC3236736  PMID: 22180726
4.  A common MYBPC3 (cardiac myosin binding protein C) variant associated with cardiomyopathies in South Asia 
Nature genetics  2009;41(2):187-191.
Heart failure is a leading cause of mortality in South Asians. However, its genetic etiology remains largely unknown1. Cardiomyopathies due to sarcomeric mutations are a major monogenic cause for heart failure (MIM600958). Here, we describe a deletion of 25 bp in the gene encoding cardiac myosin binding protein C (MYBPC3) that is associated with heritable cardiomyopathies and an increased risk of heart failure in Indian populations (initial study OR = 5.3 (95% CI = 2.3–13), P = 2 × 10−6; replication study OR = 8.59 (3.19–25.05), P = 3 × 10−8; combined OR = 6.99 (3.68–13.57), P = 4 × 10−11) and that disrupts cardiomyocyte structure in vitro. Its prevalence was found to be high (~4%) in populations of Indian subcontinental ancestry. The finding of a common risk factor implicated in South Asian subjects with cardiomyopathy will help in identifying and counseling individuals predisposed to cardiac diseases in this region.
PMCID: PMC2697598  PMID: 19151713

Results 1-4 (4)