A novel microdeletion syndrome at 9q21.13 characterised by mental retardation, speech delay, epilepsy and characteristic facial features

Boudry-Labis, Elise; Caignec, Cédric Le; Isidor, Bertrand; Mathieu‐Dramard, Michèle; Plessis, Ghislaine; George, Alice M.; Taylor, Juliet; Aftimos, Salim; Wiemer‐Kruel, Adelheid; Kohlhase, Juergen; Annerén, Göran; Firth, Helen V.; Simonic, Ingrid; Vermeesch, Joris Robert; Thuresson, Ann‐Charlotte; Copin, Henri; Love, Donald R.; Andrieux, Joris

doi:10.1016/j.ejmg.2012.12.006

Cited by 36 publications

(60 citation statements)

References 13 publications

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“…In the human genome, miR-204 is located within intron 8 of the transient receptor potential (TRP) channel gene, TRPM3 on chromosome 9q21.12. Deletions within 9q21, including those specifically encompassing the TRPM3 gene, have not been reported to cause ocular phenotypes; instead, features of mental retardation, epilepsy, speech delay, autistic behavior, and moderate facial dysmorphology have been reported (18)(19)(20)(21). This suggests that the heterozygous n.37C > T mutation may not act via haploinsufficiency but, rather, through a gain-of-function mechanism.…”

Section: Injection Of the N37c > T Mut-mir-204 Causes Severe Ocularmentioning

confidence: 86%

“…MiR-204 is located within intron 8 of the TRP channel gene, TRPM3, on chromosome 9q21.12. Deletions within 9q21 and those specifically encompassing the TRPM3 gene have not been reported to cause ocular phenotypes, instead causing features of mental retardation, epilepsy, speech delay, autistic behavior, and moderate facial dysmorphology (18)(19)(20)(21). Deletion of this region has been described in association with an autism phenotype in a family in which a paternal deletion of exons 1-9 of TRPM3, which included MIR204, was shared by two affected sons and an unaffected daughter who were not described to have an ocular phenotype or visual symptoms.…”

Section: Discussionmentioning

confidence: 99%

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MiR-204 is responsible for inherited retinal dystrophy associated with ocular coloboma

Conte

Hadfield

Barbato

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

111

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Ocular developmental disorders, including the group classified as microphthalmia, anophthalmia, and coloboma (MAC) and inherited retinal dystrophies, collectively represent leading causes of hereditary blindness. Characterized by extreme genetic and clinical heterogeneity, the separate groups share many common genetic causes, in particular relating to pathways controlling retinal and retinal pigment epithelial maintenance. To understand these shared pathways and delineate the overlap between these groups, we investigated the genetic cause of an autosomal dominantly inherited condition of retinal dystrophy and bilateral coloboma, present in varying degrees in a large, five-generation family. By linkage analysis and exome sequencing, we identified a previously undescribed heterozygous mutation, n.37C > T, in the seed region of microRNA-204 (miR-204), which segregates with the disease in all affected individuals. We demonstrated that this mutation determines significant alterations of miR-204 targeting capabilities via in vitro assays, including transcriptome analysis. In vivo injection, in medaka fish (Oryzias latipes), of the mutated miR-204 caused a phenotype consistent with that observed in the family, including photoreceptor alterations with reduced numbers of both cones and rods as a result of increased apoptosis, thereby confirming the pathogenic effect of the n.37C > T mutation. Finally, knockdown assays in medaka fish demonstrated that miR-204 is necessary for normal photoreceptor function. Overall, these data highlight the importance of miR-204 in the regulation of ocular development and maintenance and provide the first evidence, to our knowledge, of its contribution to eye disease, likely through a gain-of-function mechanism.

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Section: Injection Of the N37c > T Mut-mir-204 Causes Severe Ocularmentioning

confidence: 86%

Section: Discussionmentioning

confidence: 99%

MiR-204 is responsible for inherited retinal dystrophy associated with ocular coloboma

Conte

Hadfield

Barbato

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

111

View full text Add to dashboard Cite

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“…None of the other potentially pathogenic variants found by WES were shared by all four affected individuals. In addition, none of the variants of potential interest identified by WES that were common to the four family members with PPR (4,13,20,21) were found in the remaining family members with PPR (10, 11, 14, 15, and 23) by Sanger sequencing. Further details are in the Supplementary Table S2.…”

Section: Resultsmentioning

confidence: 99%

“…We and others [21][22][23] have identified de novo 9q21 microdeletions including RORB in patients with epilepsy of variable semiology. Of the 16 patients with 9q21 deletions reported in the literature, all patients have mild-to-moderate ID and speech delay, and a subset of patients had behavioral abnormality (9/16) and epilepsy (14/16).…”

Section: Discussionmentioning

confidence: 99%

Loss of function of the retinoid-related nuclear receptor (RORB) gene and epilepsy

et al. 2016

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Genetic generalized epilepsy (GGE), formerly known as idiopathic generalized epilepsy, is the most common form of epilepsy and is thought to have predominant genetic etiology. GGE are clinically characterized by absence, myoclonic, or generalized tonic-clonic seizures with electroencephalographic pattern of bilateral, synchronous, and symmetrical spike-and-wave discharges. Despite their strong heritability, the genetic basis of generalized epilepsies remains largely elusive. Nevertheless, recent advances in genetic technology have led to the identification of numerous genes and genomic defects in various types of epilepsies in the past few years. In the present study, we performed whole-exome sequencing in a family with GGE consistent with the diagnosis of eyelid myoclonia with absences. We found a nonsense variant (c.196C4T/p.(Arg66*)) in RORB, which encodes the beta retinoid-related orphan nuclear receptor (RORβ), in four affected family members. In addition, two de novo variants (c.218T4C/p.(Leu73Pro); c.1249_1251delACG/p.(Thr417del)) were identified in sporadic patients by trio-based exome sequencing. We also found two de novo deletions in patients with behavioral and cognitive impairment and epilepsy: a 52-kb microdeletion involving exons 5-10 of RORB and a larger 9q21-microdeletion. Furthermore, we identified a patient with intellectual disability and a balanced translocation where one breakpoint truncates RORB and refined the phenotype of a recently reported patient with RORB deletion. Our data support the role of RORB gene variants/CNVs in neurodevelopmental disorders including epilepsy, and especially in generalized epilepsies with predominant absence seizures.

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“…Recently, more than dozen patients have been reported with novel chromosome microdeletions at 9q21.13, presenting mental retardation, speech delay, and epilepsy (49,50). The smallest region of deletion contained six genes, including that encoding human UPF0586 (also known as C9orf41).…”

Section: Methylmentioning

confidence: 99%

UPF0586 Protein C9orf41 Homolog Is Anserine-producing Methyltransferase

Drożak

Piecuch

Poleszak

et al. 2015

Journal of Biological Chemistry

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Background:Anserine is an abundant dipeptide in vertebrate skeletal muscles. Results: We identified UPF0586 protein C9orf41 homolog as a carnosine N-methyltransferase, responsible for anserine formation in rat muscle. Conclusion: Besides being a carnosine N-methyltransferase, UPF0586 protein is likely to be a novel peptide or protein methyltransferase in eukaryotes. Significance: This molecular identification will help to elucidate physiological functions of UPF0586 protein in eukaryotes.

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A novel microdeletion syndrome at 9q21.13 characterised by mental retardation, speech delay, epilepsy and characteristic facial features

Cited by 36 publications

References 13 publications

MiR-204 is responsible for inherited retinal dystrophy associated with ocular coloboma

MiR-204 is responsible for inherited retinal dystrophy associated with ocular coloboma

Loss of function of the retinoid-related nuclear receptor (RORB) gene and epilepsy

UPF0586 Protein C9orf41 Homolog Is Anserine-producing Methyltransferase

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