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.

ISPD gene homozygous deletion identified by SNP array confirms prenatal manifestation of Walker–Warburg syndrome

“…While the WWS phenotype of the affected individuals with ISPD mutations was described for postnatal cases [Cirak et al, 2013;Czeschik et al, 2013;Roscioli et al, 2012;Willer et al, 2012], only few prenatal cases were published [Vuillaumier-Barrot et al, 2012]. We report two prenatally detected ISPD gene deletions in foetuses with multiple brain anomalies that corresponded to the WWS phenotype.…”

“…The mechanism by which ISPD gene mutations lead to a reduction of a-dystroglycan glycosylation is not well understood; however, the pivotal role of ISPD in the initial step of Omannosylation of -a-dystroglycan was recently described. Omannosylation is an important step in glycosylation and is essential for the interaction of a-dystroglycan with extracellular matrix proteins, such as laminin-a2 [Cirak et al, 2013]. Six studies of the ISPD gene mutations in patients with cobblestone lissencephaly [Vuillaumier-Barrot et al, 2012], WWS [Czeschik et al, 2013;Roscioli et al, 2012;Willer et al, 2012] and congenital and limb-girdle muscular dystrophies [Baranello et al, 2015;Cirak et al, 2013] have been published, and multiple rare variants were found in 29 independent families.…”

“…Omannosylation is an important step in glycosylation and is essential for the interaction of a-dystroglycan with extracellular matrix proteins, such as laminin-a2 [Cirak et al, 2013]. Six studies of the ISPD gene mutations in patients with cobblestone lissencephaly [Vuillaumier-Barrot et al, 2012], WWS [Czeschik et al, 2013;Roscioli et al, 2012;Willer et al, 2012] and congenital and limb-girdle muscular dystrophies [Baranello et al, 2015;Cirak et al, 2013] have been published, and multiple rare variants were found in 29 independent families. All affected individuals with homozygous segmental intragenic deletion of the ISPD gene exhibited progressive muscular dystrophy with a severe WWS phenotype, including hydrocephalus, cobblestone lissencephaly of the cerebral cortex, severe brainstem hypoplasia and hypoplasia of the cerebellum cases [Roscioli et al, 2012;Willer et al, 2012].…”

MotorPlex provides accurate variant detection across large muscle genes both in single myopathic patients and in pools of DNA samples

“…In families with patients who are more severely affected, this "grey area" is problematic for both genetic counselling and forthcoming mutation-specific treatments. However, this represents the proper challenge for the new genomic, high-throughput technologies: the power of discovery has been dramatically boosted by the introduction of the next-generation sequencing (NGS) techniques [13,[36][37][38]. In the NGS era, the genetic testing is going to move from few candidate genes to broader panels of genes [39] or, ultimately, to the entire genome.…”

Cerebellar Cysts in Children: A Pattern-Recognition Approach

“…Cirak et al reported ISPD mutations in dystroglycanopathy phenotypes milder compared to WWS, namely ambulant patients with limb-girdle muscular dystrophy [35]. One child (patient 6) was found to have multiple cerebellar cysts.…”