A novel homozygous ISPD gene mutation causing phenotype variability in a consanguineous family

Baranello, Giovanni; Saredi, Simona; Sansanelli, Serena; Savadori, Paolo; Canioni, Eleonora; Chiapparini, Luisa; Balestri, Paolo; Malandrini, Alessandro; Arnoldi, Maria Teresa; Pantaleoni, Chiara; Morandi, Lucia; Mora, Marina

doi:10.1016/j.nmd.2014.08.007

Cited by 7 publications

(4 citation statements)

References 17 publications

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“…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].…”

Section: Discussionmentioning

confidence: 99%

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

Trkova

Krutilkova

Smetanová

et al. 2015

European Journal of Medical Genetics

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Section: Discussionmentioning

confidence: 99%

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

Trkova

Krutilkova

Smetanová

et al. 2015

European Journal of Medical Genetics

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“…Regarding other genes responsible for secondary dystroglycanopathies, only sporadic cases with LGMD phenotype have been reported thus far [ 10 , 16 , 21 , 25 – 28 ]. In particular, ISPD mutations appear to be responsible for a relatively high proportion of dystroglycanopathies within the most severe clinical spectrum [ 13 , 14 , 17 ], although they have also been described in a few LGMD cases [ 28 – 30 ].…”

Section: Discussionmentioning

confidence: 99%

“…According to this description, forms of LGMD caused by mutations in ISPD are described as LGMD2S [ 2 ]. Intra-familial variability has also been described [ 30 ].…”

Section: Introductionmentioning

confidence: 99%

ISPD mutations account for a small proportion of Italian Limb Girdle Muscular Dystrophy cases

Magri

Colombo

et al. 2015

BMC Neurol

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BackgroundLimb Girdle Muscular Dystrophy (LGMD), caused by defective α-dystroglycan (α-DG) glycosylation, was recently associated with mutations in Isoprenoid synthase domain-containing (ISPD) and GDP-mannose pyrophosphorylase B (GMPPB) genes. The frequency of ISPD and GMPPB gene mutations in the LGMD population is unknown.MethodsWe investigated the contributions of ISPD and GMPPB genes in a cohort of 174 Italian patients with LGMD, including 140 independent probands. Forty-one patients (39 probands) from this cohort had not been genetically diagnosed. The contributions of ISPD and GMPPB were estimated by sequential α-DG immunohistochemistry (IHC) and mutation screening in patients with documented α-DG defect, or by direct DNA sequencing of both genes when muscle tissue was unavailable.ResultsWe performed α-DG IHC in 27/39 undiagnosed probands: 24 subjects had normal α-DG expression, two had a partial deficiency, and one exhibited a complete absence of signal. Direct sequencing of ISPD and GMPPB revealed two heterozygous ISPD mutations in the individual who lacked α-DG IHC signal: c.836-5 T > G (which led to the deletion of exon 6 and the production of an out-of-frame transcript) and c.676 T > C (p.Tyr226His). This patient presented with sural hypertrophy and tip-toed walking at 5 years, developed moderate proximal weakness, and was fully ambulant at 42 years. The remaining 12/39 probands did not exhibit pathogenic sequence variation in either gene.ConclusionISPD mutations are a rare cause of LGMD in the Italian population, accounting for less than 1 % of the entire cohort studied (FKRP mutations represent 10 %), while GMPPB mutations are notably absent in this patient sample. These data suggest that the genetic heterogeneity of LGMD with and without α-DG defects is greater than previously realized.Electronic supplementary materialThe online version of this article (doi:10.1186/s12883-015-0428-8) contains supplementary material, which is available to authorized users.

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“…More than twenty-five individuals have been reported, evenly distributed from the most severe clinical presentation, LIS II [68] and WWS [66,70], to milder forms such as LGMD [71,72]. [53] and that has not been assigned any function.…”

Section: -Ispd (Omim 614631)mentioning

confidence: 99%

Dystroglycanopathies: About Numerous Genes Involved in Glycosylation of One Single Glycoprotein

Bouchet-Seraphin

Vuillaumier‐Barrot

Seta

2015

Journal of Neuromuscular Diseases

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Dystroglycanopathies are neuromuscular disorders due to abnormal glycosylation of dystroglycan which is a cellsurface glycoprotein that acts as a receptor for extracellular matrix proteins containing laminin-G domains. The reduced ability of abnormally glycosylated ␣−DG to bind laminin is associated with abnormal neuronal migration and muscular dystrophy. Clinical manifestations are extremely variable, and include a wide spectrum of phenotypic severity: some mutations are associated with adult-onset Limb-girdle muscular dystrophy and other mutations with a congenital onset, determining the more complex disorder Congenital Muscular Dystrophy which includes severe structural brain and eye anomalies such as Muscle-Eye-Brain Disease, Walker-Warburg Syndrome, and Fukuyama Congenital Muscular Dystrophy. So far, mutations in eighteen different genes have been identified in patients with dystroglycanopathies, all of them demonstrating autosomal recessive inheritance. Most genes code for glycosyltransferases (POMT1, POMT2, POMGNT1, LARGE, GTDC2, B4GAT1, B3GALNT2) although a minority does not (DPM1, DPM2, DPM3, DOLK, POMK, GMPPB). Others genes code for proteins of unknown function in the ␣−dystroglycan glycosylation (FKTN, FKRP, ISPD, and TMEM5) or ␣−dystroglycan itself, DAG1. The biochemical picture becomes a little bit more complete, but also more complex, with each new identified gene. In the majority of cases the identity of the defective gene cannot be predicted from the clinical phenotype. Considering the number of causative genes in dystroglycanopathies, targeted sequencing comprising genes of all glycosylation, whatever the type, would appear at present to be the best way of tackling molecular diagnosis.

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A novel homozygous ISPD gene mutation causing phenotype variability in a consanguineous family

Cited by 7 publications

References 17 publications

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

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

ISPD mutations account for a small proportion of Italian Limb Girdle Muscular Dystrophy cases

Dystroglycanopathies: About Numerous Genes Involved in Glycosylation of One Single Glycoprotein

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