Intragenic deletion in the LARGE gene causes Walker-Warburg syndrome

Reeuwijk, Jeroen van; Grewal, Prabhjit K.; Salih, Mustafa A.; Bernabé, Daniel Beltrán-Valero de; McLaughlan, Jenny M.; Michielse, Caroline B.; Herrmann, Ralf; Hewitt, Jane; Steinbrecher, Alice; Seidahmed, Mohamed Z.; Shaheed, Mohamed M.; Abomelha, Abdullah M.; Brunner, Han G.; Bokhoven, Hans van; Voït, Thomas

doi:10.1007/s00439-007-0362-y

Cited by 128 publications

(80 citation statements)

References 28 publications

(38 reference statements)

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“…Residual glycosylated aDG staining was present in the muscle biopsy, and both sisters have less severe cognitive deficits and brain malformations than a patient with homozygous null mutations in LARGE who had a WWS phenotype. 7 We also detected low levels of a normally spliced LARGE gene mRNA transcript in both lymphoblasts and fibroblasts, which should allow normal LARGE protein to be produced at low levels.…”

Section: Discussionmentioning

confidence: 71%

“…6,8 Although experience is very limited at present, it is notable that two of the four confirmed families with CMD, caused by LARGE mutation, have had large gene rearrangements, either a deletion involving several exons 7 or a likely intragenic insertion/deletion (our family). In another family, a heterozygous nonsense mutation (p.Trp516X) was identified on standard gene sequencing, leaving open the possibility that a large deletion/duplication or rearrangement on the other allele was overlooked.…”

Section: Discussionmentioning

confidence: 92%

“…MDC1D due to mutations in LARGE is the rarest of the adystroglycanopathies identified to date, with only three confirmed families previously described. [6][7][8] Affected children have had typical neurological and muscle abnormalities associated with the a-dystroglycanopathies, but with very different severities; one family had mild muscle-eye-brain disease (MEB) and the other two had typical WWS. Another WWS patient has been reported with a single heterozygous nonsense mutation in LARGE.…”

Section: Introductionmentioning

confidence: 99%

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Congenital muscular dystrophy type 1D (MDC1D) due to a large intragenic insertion/deletion, involving intron 10 of the LARGE gene

et al. 2011

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Mutation of the LARGE gene is the rarest of the six known genetic causes of a-dystroglycanopathy. We report further a family with MDC1D due to a complex genomic rearrangement that was not apparent on standard sequencing of LARGE. Two sisters in a consanguineous family had moderate mental retardation and cerebellar malformations, together with dystrophic changes and markedly reduced a-dystroglycan glycosylation staining on muscle biopsy. There was homozygous linkage to the LARGE locus but sequencing of LARGE coding regions was normal. Analysis of LARGE cDNA showed an abnormal sequence inserted between exons 10 and 11, in most of the transcripts, predicted to introduce a premature stop codon. The abnormal sequence mapped to a spliced EST (DA935254) of unknown function, normally located at 100 kb centromeric of LARGE on chromosome 22q12.3. Quantitative PCR analysis of the EST and adjacent regions showed twice the normal copy number in patients' genomic DNA samples, consistent with a large intra-chromosomal duplication inserted into intron 10 of LARGE in a homozygous state. This insertion was associated with deletion of a central region of intron 10, but the exact break points of the deletion/ duplication were not found, suggesting that an even more complex rearrangement may have occurred. The exact function of LARGE, a golgi protein, remains uncertain. POMT and POMGnT enzyme activities were normal in patients' lymphoblast cells, suggesting that defects in LARGE do not affect the initiation of O-mannosyl glycans.

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Section: Discussionmentioning

confidence: 71%

Section: Discussionmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

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Congenital muscular dystrophy type 1D (MDC1D) due to a large intragenic insertion/deletion, involving intron 10 of the LARGE gene

et al. 2011

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“…12 It is the main CNS feature of CMDs with O-glycosylation defects of ␣-dystroglycan, even though it is difficult to differentiate the genetic causes on the basis of brain MRI because of overlapping phenotypes. [19][20][21][22][23] Cerebral, cerebellar, and brainstem abnormalities have been well documented in the major phenotypes: FCMD, WWS, and MEB. WWS displays severe cerebral cortical dysplasia, hypomyelination, dysplastic tectum, pontomedullary kink, severe hypoplasia of the vermis, and dysplastic cerebellar hemispheres.…”

Section: Resultsmentioning

confidence: 99%

Midbrain–hindbrain involvement in lissencephalies

Jissendi-Tchofo¹,

Kara²,

Barkovich³

2009

Neurology

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Objectives:To determine the involvement of the midbrain and hindbrain (MHB) in the groups of classic (cLIS), variant (vLIS), and cobblestone complex (CBSC) lissencephalies and to determine whether a correlation exists between the cerebral malformation and the MHB abnormalities.Methods: MRI scans of 111 patients (aged 1 day to 32 years; mean 5 years 4 months) were retrospectively reviewed. After reviewing the brain involvement on MRI, the cases were reclassified according to known mutation (LIS1, DCX, ARX, VLDLR, RELN, MEB, WWS) or mutation phenotype (LIS1-P, DCX-P, RELN-P, ARX-P, VLDLR-P) determined on the basis of characteristic MRI features. Abnormalities in the MHB were then recorded. For each structure, a score was assigned, ranging from 0 (normal) to 3 (severely abnormal). The differences between defined groups and the correlation between the extent of brain agyria/pachygyria and MHB involvement were assessed using Kruskal-Wallis and 2 McNemar tests. Results:There was a significant difference in MHB appearance among the three major groups of cLIS, vLIS, and CBSC. The overall score showed a severity gradient of MHB involvement: cLIS (0 or 1), vLIS (7), and CBSC (11 or 12). The extent of cerebral lissencephaly was significantly correlated with the severity of MHB abnormalities (p ϭ 0.0029). Conclusion: GLOSSARYA ϭ autosomal; ACC ϭ agenesis of corpus callosum; AD ϭ autosomal dominant; AP ϭ anteroposterior; AR ϭ autosomal recessive; CBL ϭ cerebellar; CBSC ϭ cobblestone complex; cLIS ϭ classic lissencephaly; CMD ϭ congenital muscular dystrophy; CSZ ϭ cell-sparse zone; DV ϭ dorsal-ventral; FCMD ϭ Fukuyama congenital muscular dystrophy; IVH ϭ inferior vermis hypoplasia; LV ϭ lateral ventricle; m ϭ medulla; M ϭ midbrain; MDS ϭ Miller-Dieker syndrome; MEB ϭ muscle-eyebrain; MHB ϭ midbrain and hindbrain; MR ϭ magnetic resonance; ND ϭ not determined; P ϭ pons; RC ϭ rostrocaudal; SCBH ϭ subcortical band heterotopia; SELH ϭ subependymal linear heterotopia; V ϭ vermis; vLIS ϭ variant lissencephaly; WI ϭ weighted image; WWS ϭ Walker-Warburg syndrome; XLD ϭ X-linked dominant; XLR ϭ X-linked recessive.The term lissencephaly (smooth outer brain surface) refers to a paucity of gyral and sulcal development. 1 It encompasses a spectrum of gyral malformations ranging from complete agyria to regional pachygyria and includes subcortical band heterotopia. Lissencephaly has been traditionally classified in two distinct groups: classic (cLIS, formerly called lissencephaly type 1) and cobblestone complex (CBSC, formerly called lissencephaly type 2) based on both brain imaging and pathology. To date, five genes have been identified as causing or contributing to human cLIS: LIS1, 14-3-3 in Miller-Dieker syndrome (MDS), DCX, RELN, and ARX. [1][2][3][4][5][6] A new classification has recently been proposed defining four groups of cLIS differing from each other by genetics and neuropathologic features of the cerebral cortex, cerebellum, and brainstem. 3 1)

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“…Defects of O-mannosylation belong to dystroglycanopathies, since -dystroglycan is the main carrier [61,62]. However, the severity of the disease depends more on the level of residual activity of the enzymes than on the position of the mutated gene along the glycosylation pathway.…”

Section: Defects Of O-man Glycosylationmentioning

confidence: 99%

Diseases of glycosylation beyond classical congenital disorders of glycosylation

Hennet

2012

Biochimica et Biophysica Acta (BBA) - General Subjects

116

103

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BACKGROUND: Diseases of glycosylation are rare inherited disorders, which are often referred to as congenital disorders of glycosylation (CDG). Several types of CDG have been described in the last decades, encompassing defects of nucleotide-sugar biosynthesis, nucleotide-sugar transporters, glycosyltransferases and vesicular transport. Although clinically heterogeneous, most types of CDG are associated with neurological impairments ranging from severe psychomotor retardation to moderate intellectual disabilities. CDG are mainly caused by defects of N-glycosylation, owing to the simple detection of under-glycosylated serum transferrin by isoelectric focusing. SCOPE OF REVIEW: In the last years, several disorders of O-glycosylation, glycolipid and glycosaminoglycan biosynthesis have been described, which are known by trivial names not directly associated with the family of CDG. The present review outlines 64 gene defects affecting glycan biosynthesis and modifications, thereby underlining the complexity of glycosylation pathways and pointing to unexpected phenotypes and functional redundancies in the control of glycoconjugate biosynthesis. MAJOR CONCLUSIONS: The increasing application of whole-genome sequencing techniques unravels new defects of glycosylation, which are associated to moderate forms of mental disabilities. GENERAL SIGNIFICANCE: The knowledge gathered through the investigation of CDG increases the understanding of the functions associated to protein glycosylation in humans. This article is part of a Special Issue entitled Glycoproteomics.

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Intragenic deletion in the LARGE gene causes Walker-Warburg syndrome

Cited by 128 publications

References 28 publications

Congenital muscular dystrophy type 1D (MDC1D) due to a large intragenic insertion/deletion, involving intron 10 of the LARGE gene

Congenital muscular dystrophy type 1D (MDC1D) due to a large intragenic insertion/deletion, involving intron 10 of the LARGE gene

Midbrain–hindbrain involvement in lissencephalies

Diseases of glycosylation beyond classical congenital disorders of glycosylation

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