title: ISPD gene mutations are a common cause of congenital and limb-girdle muscular dystrophies.
abstract: Dystroglycanopathies are a clinically and genetically diverse group of recessively inherited conditions ranging from the most severe of the congenital muscular dystrophies, Walker-Warburg syndrome, to mild forms of adult-onset limb-girdle muscular dystrophy. Their hallmark is a reduction in the functional glycosylation of α-dystroglycan, which can be detected in muscle biopsies. An important part of this glycosylation is a unique O-mannosylation, essential for the interaction of α-dystroglycan with extracellular matrix proteins such as laminin-α2. Mutations in eight genes coding for proteins in the glycosylation pathway are responsible for ∼50% of dystroglycanopathy cases. Despite multiple efforts using traditional positional cloning, the causative genes for unsolved dystroglycanopathy cases have escaped discovery for several years. In a recent collaborative study, we discovered that loss-of-function recessive mutations in a novel gene, called isoprenoid synthase domain containing (ISPD), are a relatively common cause of Walker-Warburg syndrome. In this article, we report the involvement of the ISPD gene in milder dystroglycanopathy phenotypes ranging from congenital muscular dystrophy to limb-girdle muscular dystrophy and identified allelic ISPD variants in nine cases belonging to seven families. In two ambulant cases, there was evidence of structural brain involvement, whereas in seven, the clinical manifestation was restricted to a dystrophic skeletal muscle phenotype. Although the function of ISPD in mammals is not yet known, mutations in this gene clearly lead to a reduction in the functional glycosylation of α-dystroglycan, which not only causes the severe Walker-Warburg syndrome but is also a common cause of the milder forms of dystroglycanopathy.
authors.affiliation: Dubowitz Neuromuscular Centre, UCL Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, UK.
authors.forename: Sebahattin
authors.initials: S
authors.lastname: Cirak
authors.forename: Aileen Reghan
authors.initials: AR
authors.lastname: Foley
authors.forename: Ralf
authors.initials: R
authors.lastname: Herrmann
authors.forename: Tobias
authors.initials: T
authors.lastname: Willer
authors.forename: Shu
authors.initials: S
authors.lastname: Yau
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Stevens
authors.forename: Silvia
authors.initials: S
authors.lastname: Torelli
authors.forename: Lina
authors.initials: L
authors.lastname: Brodd
authors.forename: Alisa
authors.initials: A
authors.lastname: Kamynina
authors.forename: Petr
authors.initials: P
authors.lastname: Vondracek
authors.forename: Helen
authors.initials: H
authors.lastname: Roper
authors.forename: Cheryl
authors.initials: C
authors.lastname: Longman
authors.forename: Rudolf
authors.initials: R
authors.lastname: Korinthenberg
authors.forename: Gianni
authors.initials: G
authors.lastname: Marrosu
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Michele
authors.forename: Vincent
authors.initials: V
authors.lastname: Plagnol
authors.forename: Matt
authors.initials: M
authors.lastname: Hurles
authors.forename: Steven A
authors.initials: SA
authors.lastname: Moore
authors.forename: Caroline A
authors.initials: CA
authors.lastname: Sewry
authors.forename: Kevin P
authors.initials: KP
authors.lastname: Campbell
authors.forename: Thomas
authors.initials: T
authors.lastname: Voit
authors.forename: Francesco
authors.initials: F
authors.lastname: Muntoni
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D049030:Dystroglycans / Q000235:genetics / Q000378:metabolism; D005260:Female; D006031:Glycosylation; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D009136:Muscular Dystrophies / Q000151:congenital* / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D049288:Muscular Dystrophies, Limb-Girdle / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D009713:Nucleotidyltransferases / Q000235:genetics*; D055815:Young Adult
chemical_list: D049030:Dystroglycans; D009713:Nucleotidyltransferases; C573136:CRPPA protein, human