Novel genetic causes for cerebral visual impairment

Bosch, Daniëlle G.M.; Boonstra, F. Nienke; Leeuw, Nicole de; Pfundt, Rolph; Nillesen, Willy M.; Ligt, Joep de; Gilissen, Christian; Jhangiani, Shalini N.; Lupski, James R.; Cremers, Frans P.M.; Vries, Bert B.A. de

doi:10.1038/ejhg.2015.186

Cited by 131 publications

(142 citation statements)

References 78 publications

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“…Thus far, all six variants identified in the S1 region are missense de novo mutations in patients with ID, EE, and ASD (12,13,16,24,34,54), whereas 4 of 13 variants in the S2 domain produce a frameshift or introduce a stop codon. Eleven of twelve variants in S2 are de novo mutations in patients with mild to severe ID, DD, ASD or cerebral visual impairment with or without epileptic features (7,11–13,15,17,20,23,24,26,29,54). None of these S1 or S2 ABD mutations are found in the Exome Aggregation Consortium (ExAC) dataset (35, Table 1, Fig.…”

Section: Grin2b Mutations In Agonist-binding Domain (Abd)mentioning

confidence: 99%

“…It is notable and consistent with these protein truncation variants that many of the missense ABD variants, likewise, when expressed in in vitro systems, show substantial reductions in cell surface NMDAR expression (Table 1, 54). Multiple additional missense or nonsense de novo mutations in the ABD S2 (p.Gln662Pro, p.Arg682Cys, p.Thr685Pro, p.Pro687Arg, p.Gly689Ser, p.Arg696His, p.Met706Val, and p.Gln711X) have been identified in patients with ID, DD, ASD, cerebral visual impairment, and epilepsy with functional studies reported in just two cases, both which increase glutamate potency (11,12,15,17,21,26,54). Given these mutations reside in the ABD S2, and the variant mutation introduces non-conservative amino acids into the ABD, we anticipate many of these variants are likely to alter GluN2B agonist potency and GluN2B subunit function and thus may contribute to the patient phenotype.…”

Section: Grin2b Mutations In Agonist-binding Domain (Abd)mentioning

confidence: 99%

“…GRIN2B variants and de novo nonsynonymous mutations with neurological disease has recently been reviewed (55,56). Here we review all missense, nonsense, frameshift, or splice site GRIN2B mutations identified in individuals from patient cohorts with defined neurodevelopmental and psychiatric disorders such as ID and DD (7,9–15,17,18,21,29,54), EE (7,13,15,16,53,54), ASD (18–20,22–26,54), SCZ (19,20,26,27), AD(28), and CVI (11). The GRIN2B variants identified thus far occurred throughout the entire NMDAR subunit protein.…”

Section: Introductionmentioning

confidence: 99%

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Human GRIN2B variants in neurodevelopmental disorders

Chen

Myers

et al. 2016

Journal of Pharmacological Sciences

179

143

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The development of whole exome/genome sequencing technologies has given rise to an unprecedented volume of data linking patient genomic variability to brain disorder phenotypes. A surprising number of variants have been found in the N-methyl-D-aspartate receptor (NMDAR) gene family, with the GRIN2B gene encoding the GluN2B subunit being implicated in many cases of neurodevelopmental disorders, which are psychiatric conditions originating in childhood and include language, motor, and learning disorders, autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), developmental delay, epilepsy, and schizophrenia. The GRIN2B gene plays a crucial role in normal neuronal development and is important for learning and memory. Mutations in human GRIN2B were distributed throughout the entire gene in a number of patients with various neuropsychiatric and developmental disorders. Studies that provide functional analysis of variants are still lacking, however current analysis of de novo variants that segregate with disease cases such as intellectual disability, developmental delay, ASD or epileptic encephalopathies reveal altered NMDAR function. Here, we summarize the current reports of disease-associated variants in GRIN2B from patients with multiple neurodevelopmental disorders, and discuss implications, highlighting the importance of functional analysis and precision medicine therapies.

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Section: Grin2b Mutations In Agonist-binding Domain (Abd)mentioning

confidence: 99%

Section: Grin2b Mutations In Agonist-binding Domain (Abd)mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Human GRIN2B variants in neurodevelopmental disorders

Chen

Myers

et al. 2016

Journal of Pharmacological Sciences

179

143

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show abstract

“…It is remarkable that all cases were detected by WES after several genetic tests. Clinical features of the reported cases of Xia et al [2014], Yang et al [2015], and Bosch et al [2016] compared with the clinical presentation of our case are summarized in Table 1 . Xia et al [2014] proposed that AHDC1 -associated ID is due to a dominant-negative mechanism, given the autosomal-dominant inheritance and the single coding exon of this gene .…”

Section: Discussionmentioning

confidence: 99%

“…Yang et al [2015] reported 6 frameshifts or nonsense deleterious de novo variants and 1 recurrent variant in the same gene, associated with expressive language delay, hypotonia, and sleep apnea. Recently, Bosch et al [2016] identified a de novo variant in an older patient with a history of DD and speech delay as well as characteristic facies. Previously, a de novo missense variant in a case of schizophrenia [Guipponi et al, 2014] and a de novo balanced translocation with a breakpoint in the AHDC1 intron 1 in a boy with bicuspid aortic valve, aortic coarctation, patent ductus arteriosus, and DD/ID have been reported in this gene [Quintero-Rivera et al, 2015].…”

mentioning

confidence: 99%

Whole-Exome Sequencing Identifies a de novo AHDC1 Mutation in a Colombian Patient with Xia-Gibbs Syndrome

García-Acero

Acosta²

2017

Mol Syndromol

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Xia-Gibbs syndrome is an autosomal dominant multisystem developmental disorder characterized by global developmental delay, hypotonia, obstructive sleep apnea, seizures, retrocerebellar cysts, delayed myelination, micrognathia, and mild dysmorphic features. Using whole-exome sequencing, we identified a de novo AHDC1 frameshift mutation c.2030_2030delG (p.G677Afs*52) in a Colombian patient, which was absent in both parents. Furthermore, we summarized the phenotypes of patients reported in the literature.

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An Induced Pluripotent Stem Cell‐Derived Neuromuscular Junction Platform for Study of the NGLY1‐Congenital Disorder of Deglycosylation

Sasserath

Robertson

Mendez

et al. 2022

Advanced Therapeutics

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There are many neurological rare diseases where animal models have proven inadequate or do not currently exist. NGLY1 deficiency, a congenital disorder of deglycosylation, is a rare disease that predominantly affects motor control, especially control of neuromuscular action. In this study, NGLY1-deficient, patient-derived induced pluripotent stem cells (iPSCs) are differentiated into motoneurons (MNs) to identify disease phenotypes analogous to clinical disease pathology with significant deficits apparent in the NGLY1-deficient lines compared to the control. A neuromuscular junction (NMJ) model is developed using patient and wild type MNs to study functional differences between healthy and diseased NMJs. Reduced axon length, increased and shortened axon branches, MN action potential (AP) bursting, and decreased AP firing rate and amplitude are observed in the NGLY1-deficient MNs in monoculture. When transitioned to the NMJ-coculture system, deficits in NMJ number, stability, failure rate, and synchronicity with indirect skeletal muscle stimulation are observed. This project establishes a phenotypic NGLY1 model for investigation of possible therapeutics and investigations into mechanistic deficits in the system.

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Novel genetic causes for cerebral visual impairment

Cited by 131 publications

References 78 publications

Human GRIN2B variants in neurodevelopmental disorders

Human GRIN2B variants in neurodevelopmental disorders

Whole-Exome Sequencing Identifies a de novo AHDC1 Mutation in a Colombian Patient with Xia-Gibbs Syndrome

An Induced Pluripotent Stem Cell‐Derived Neuromuscular Junction Platform for Study of the NGLY1‐Congenital Disorder of Deglycosylation

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