Mutations in the oligophrenin-1 gene (OPHN1) cause X linked congenital cerebellar hypoplasia

Philip, Nicole

doi:10.1136/jmg.40.6.441

Cited by 108 publications

(87 citation statements)

References 21 publications

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“…However, it is also clear CVH can also be distinct from DWM. For example, mutations in Oligophrenin 1 (OPHN1), a widely expressed gene encoding a rhoGAP protein, cause X-linked mental retardation and CVH, but never DWM [62][63][64]. In vitro and in vivo experiments have demonstrated a role for Ophn1 in dendritic spine morphogensis in hippocampal neurons in mice, although no gross cerebellar anatomical abnormalities were observed in Ophn1 mutant mice [65,66].…”

Section: Dandy-walker Malformation and Cerebellar Vermis Hypoplasiamentioning

confidence: 99%

Cerebellar development and disease

Millen¹,

Gleeson²

2008

Current Opinion in Neurobiology

170

141

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The molecular control of cell type specification within the developing cerebellum as well as the genetic causes of the most common human developmental cerebellar disorders have long remained mysterious. Recent genetic lineage and loss-of-function data from mice have revealed unique and non-overlapping anatomical origins for GABAergic neurons from ventricular zone precursors and glutamatergic cell from rhombic lip precursors, mirroring distinct origins for these neurotransmitterspecific cell types in the cerebral cortex. Mouse studies elucidating the role of Ptf1a as a cerebellar ventricular zone GABerigic fate switch were actually preceded by the recognition that PTF1A mutations in humans cause cerebellar agenesis, a birth defect of the human cerebellum. Indeed, several genes for congenital human cerebellar malformations have recently been identified, including genes causing Joubert syndrome, Dandy-Walker malformation and Ponto-cerebellar hypoplasia. These studies have pointed to surprisingly complex roles for transcriptional regulation, mitochondrial function and neuronal cilia in patterning, homeostasis and cell proliferation during cerebellar development. Together mouse and human studies are synergistically advancing our understanding of the developmental mechanisms that generate the uniquely complex mature cerebellum.

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Section: Dandy-walker Malformation and Cerebellar Vermis Hypoplasiamentioning

confidence: 99%

Cerebellar development and disease

Millen¹,

Gleeson²

2008

Current Opinion in Neurobiology

170

141

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“…More recently, however, the presence of OPHN1 mutations have as well been documented in families with syndromic forms of MR. Most of these patients share in common that in addition to cognitive impairment, they display cerebellar hypoplasia with vermian dysplasia and/or epilepsy [5,66,79,90]. In addition, some of these patients showed signs of strabismus, macrocephaly, hypogenitalism, hyperactivity, anxiety, and in some rare cases ataxia.…”

Section: Oligophrenin-1mentioning

confidence: 99%

Rho-linked genes and neurological disorders

Kasri

Aelst

2007

Pflugers Arch - Eur J Physiol

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Mental retardation (MR) is a common cause of intellectual disability and affects approximately 2 to 3 % of children and young adults. MR has been consistently associated with changes in dendrites and dendritic spine structure. Given that dendritic spine morphology has been tightly linked to synaptic activity, altered spine morphology has been suggested to be the underlying cause of cognitive disabilities observed in MR. The structure and dynamics of dendritic spines is determined by its underlying actin cytoskeleton. Signaling molecules and cascades important for cytoskeletal regulation have therefore naturally attracted a great deal of attention. As key regulators of both the actin and microtubule cytoskeletons, it is not surprising that the Rho GTPases have emerged as important regulators of dendrite and spine structural plasticity. In support of this, mutations in regulators and effectors of Rho GTPases have been associated with diseases affecting the nervous system, including MR and amyotropic lateral sclerosis (ALS). Here we will discuss Rho GTPase related genes and their signaling pathways involved in MR and ALS.

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“…Ophn1 mutations are causal for a syndromic form of CD, including cerebellum hypoplasia and an expansion of lateral ventricles [6][7][8]. Some of these phenotypes are reproduced in Ophn1 mutant mice [9].…”

Section: Introductionmentioning

confidence: 99%

Lack of the presynaptic RhoGAP protein oligophrenin1 leads to cognitive disabilities through dysregulation of the cAMP/PKA signalling pathway

Khelfaoui

Gambino

Houbaert

et al. 2014

Phil. Trans. R. Soc. B

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Loss-of-function mutations in the gene encoding for the RhoGAP protein of oligophrenin-1 (OPHN1) lead to cognitive disabilities (CDs) in humans, yet the underlying mechanisms are not known. Here, we show that in mice constitutive lack of Ophn1 is associated with dysregulation of the cyclic adenosine monophosphate/phosphate kinase A (cAMP/PKA) signalling pathway in a brain-area-specific manner. Consistent with a key role of cAMP/PKA signalling in regulating presynaptic function and plasticity, we found that PKA-dependent presynaptic plasticity was completely abolished in affected brain regions, including hippocampus and amygdala. At the behavioural level, lack of OPHN1 resulted in hippocampus- and amygdala-related learning disabilities which could be fully rescued by the ROCK/PKA kinase inhibitor fasudil. Together, our data identify OPHN1 as a key regulator of presynaptic function and suggest that, in addition to reported postsynaptic deficits, loss of presynaptic plasticity contributes to the pathophysiology of CDs.

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Mutations in the oligophrenin-1 gene (OPHN1) cause X linked congenital cerebellar hypoplasia

Cited by 108 publications

References 21 publications

Cerebellar development and disease

Cerebellar development and disease

Rho-linked genes and neurological disorders

Lack of the presynaptic RhoGAP protein oligophrenin1 leads to cognitive disabilities through dysregulation of the cAMP/PKA signalling pathway

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