Clinical and molecular analyses of deletion 3p25‐pter syndrome

Mowrey, Philip N.; Chorney, Michael J.; Venditti, Charles P.; Latif, Farida; Modi, William S.; Lerman, Michael I.; Zbar, Berton; Robins, David; Rogan, Peter K.; Ladda, Roger L.

doi:10.1002/ajmg.1320460604

Cited by 45 publications

(51 citation statements)

References 19 publications

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“…This young woman shows hypotonia and severe MR, features characteristic for 3p Ϫ patients, but not microcephaly, growth failure, heart and renal defects, and the 3p Ϫ typical facial abnormalities (13,14). The translocation breakpoint on chromosome X is located outside of any coding region.…”

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confidence: 89%

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The novel Rho-GTPase activating gene MEGAP / srGAP3 has a putative role in severe mental retardation

Endris

Wogatzky

Leimer

et al. 2002

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

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206

213

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In the last few years, several genes involved in X-specific mental retardation (MR) have been identified by using genetic analysis. Although it is likely that additional genes responsible for idiopathic MR are also localized on the autosomes, cloning and characterization of such genes have been elusive so far. Here, we report the isolation of a previously uncharacterized gene, MEGAP, which is disrupted and functionally inactivated by a translocation breakpoint in a patient who shares some characteristic clinical features, such as hypotonia and severe MR, with the 3p ؊ syndrome. By fluorescence in situ hybridization and loss of heterozygosity analysis, we demonstrated that this gene resides on chromosome 3p25 and is deleted in 3p ؊ patients that present MR. MEGAP͞srGAP3 mRNA is predominantly and highly expressed in fetal and adult brain, specifically in the neurons of the hippocampus and cortex, structures known to play a pivotal role in higher cognitive function, learning, and memory. We describe several MEGAP͞srGAP3 transcript isoforms and show that MEGAP͞srGAP3a and -b represent functional GTPase-activating proteins (GAP) by an in vitro GAP assay. MEGAP͞srGAP3 has recently been shown to be part of the Slit-Robo pathway regulating neuronal migration and axonal branching, highlighting the important role of MEGAP͞srGAP3 in mental development. We propose that haploinsufficiency of MEGAP͞srGAP3 leads to the abnormal development of neuronal structures that are important for normal cognitive function.

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confidence: 89%

“…Recent studies (10,12,14) indicated that patients carrying terminal deletions of chromosome 3p are associated with MR and further multiple recurring symptoms depending on the size of their deletion. The deletion size is variable but generally encompass several megabases of DNA, as shown by microsatellite analyses.…”

Section: Screening Of 3pmentioning

confidence: 99%

The novel Rho-GTPase activating gene MEGAP / srGAP3 has a putative role in severe mental retardation

Endris

Wogatzky

Leimer

et al. 2002

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

Self Cite

206

213

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“…The 3p − syndrome is characterized by MR associated with microcephaly, hypotonia, growth failure, heart and renal defects, and facial abnormalities (Mowrey et al 1993). A female patient exhibiting severe MR and hypotonia, but none of the other classical 3p − symptoms, was found to possess a balanced translocation, with one of the breakpoints mapping within the 3p − deleted region.…”

Section: Autosomal Syndromic Mrmentioning

confidence: 99%

The role of the Rho GTPases in neuronal development

Govek¹,

Newey²,

Aelst³

2005

Genes Dev.

888

799

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Our brain serves as a center for cognitive function and neurons within the brain relay and store information about our surroundings and experiences. Modulation of this complex neuronal circuitry allows us to process that information and respond appropriately. Proper development of neurons is therefore vital to the mental health of an individual, and perturbations in their signaling or morphology are likely to result in cognitive impairment. The development of a neuron requires a series of steps that begins with migration from its birth place and initiation of process outgrowth, and ultimately leads to differentiation and the formation of connections that allow it to communicate with appropriate targets. Over the past several years, it has become clear that the Rho family of GTPases and related molecules play an important role in various aspects of neuronal development, including neurite outgrowth and differentiation, axon pathfinding, and dendritic spine formation and maintenance. Given the importance of these molecules in these processes, it is therefore not surprising that mutations in genes encoding a number of regulators and effectors of the Rho GTPases have been associated with human neurological diseases. This review will focus on the role of the Rho GTPases and their associated signaling molecules throughout neuronal development and discuss how perturbations in Rho GTPase signaling may lead to cognitive disorders.

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“…Subsequent studies also found MEGAP deleted in 3p − syndrome patients that present MR. These patients exhibit in addition to MR, microcephaly, growth failure, heart and renal defects, hypotonia and facial abnormalities [59].…”

Section: Megapmentioning

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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Clinical and molecular analyses of deletion 3p25‐pter syndrome

Cited by 45 publications

References 19 publications

The novel Rho-GTPase activating gene MEGAP / srGAP3 has a putative role in severe mental retardation

The novel Rho-GTPase activating gene MEGAP / srGAP3 has a putative role in severe mental retardation

The role of the Rho GTPases in neuronal development

Rho-linked genes and neurological disorders

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