Mutations in the <i>MECP2</i> Gene Are Not a Major Cause of Rett Syndrome-Like or Related Neurodevelopmental Phenotype in Male Patients

Santos, Mónica; Temudo, Teresa; Kay, Teresa; Carrilho, Inês; Medeira, Ana; Cabral, Helena; Gomes, Roseli; Lourenço, Maria Helena; Venâncio, Margarida; Calado, Eulália; Moreira, Ana; Oliveira, Guiomar; Maciel, Patrı́cia

doi:10.1177/0883073808321043

Cited by 12 publications

(10 citation statements)

References 44 publications

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“…While each patient with a deletion encompassing 3q24 has unique features, presumably related to differences in deletion breakpoints between patients, several common features are found: developmental delay, mental retardation, and growth delay including microcephaly [124]–[126]. These three common symptoms overlap those described in a subset of PDD patients: females with Rett syndrome (where MECP2 is mutated), patients with Angelman syndrome, and male Rett syndrome-like patients in which the MECP2 gene is not implicated [127], [128].…”

Section: Discussionmentioning

confidence: 99%

DIA1R Is an X-Linked Gene Related to Deleted In Autism-1

2011

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BackgroundAutism spectrum disorders (ASDs) are frequently occurring disorders diagnosed by deficits in three core functional areas: social skills, communication, and behaviours and/or interests. Mental retardation frequently accompanies the most severe forms of ASDs, while overall ASDs are more commonly diagnosed in males. Most ASDs have a genetic origin and one gene recently implicated in the etiology of autism is the Deleted-In-Autism-1 (DIA1) gene.Methodology/Principal FindingsUsing a bioinformatics-based approach, we have identified a human gene closely related to DIA1, we term DIA1R (DIA1-Related). While DIA1 is autosomal (chromosome 3, position 3q24), DIA1R localizes to the X chromosome at position Xp11.3 and is known to escape X-inactivation. The gene products are of similar size, with DIA1 encoding 430, and DIA1R 433, residues. At the amino acid level, DIA1 and DIA1R are 62% similar overall (28% identical), and both encode signal peptides for targeting to the secretory pathway. Both genes are ubiquitously expressed, including in fetal and adult brain tissue.Conclusions/SignificanceExamination of published literature revealed point mutations in DIA1R are associated with X-linked mental retardation (XLMR) and DIA1R deletion is associated with syndromes with ASD-like traits and/or XLMR. Together, these results support a model where the DIA1 and DIA1R gene products regulate molecular traffic through the cellular secretory pathway or affect the function of secreted factors, and functional deficits cause disorders with ASD-like symptoms and/or mental retardation.

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Section: Discussionmentioning

confidence: 99%

DIA1R Is an X-Linked Gene Related to Deleted In Autism-1

2011

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“…Both Rett Syndrome in female patients and Rett-Syndrome-like neurodevelopmental disorders in male patients as well as other neurodevelopmental disorders present a wide spectrum of clinical phenotypes that share a combination of symptoms like mental retardation, autism, microcephaly, stereotypic behavior and epilepsy. Recently, mutation in MeCP2 gene is shown not to be a major cause of Rett Syndrome-like or related neurodevelopmental phenotypes in male patients, 19 and a need to identify additional novel genes is emphasized by this group. Similarly, Fragile-X Syndrome shares most of behavioral similarities with autism though many patients do not meet the diagnostic criteria for typical autism but still manifest autistic features such as delayed speech development, peculiar speech, gaze aversion, hand beating or flapping, a pervasive lack of responsiveness, bizarre responses to the environment like extreme attachment to animate and inanimate objects and dramatic mood swings related to minor changes in routine.…”

Section: Discussionmentioning

confidence: 99%

Brain-Derived Neurotrophic Factor in children with Autism Spectrum Disorder

Kasarpalkar¹,

Kothari²,

Dave³

2014

ANS

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BackgroundAutism Spectrum Disorder (ASD) is a complex neurobehavioral syndrome with no known biomarker so far for early detection. It has been challenging, both to classify typical autism and associate a suitable biomarker with clinical phenotype spectrum. Brain-derived neurotrophic factor (BDNF) has emerged as a key neurotrophin regulating synaptic plasticity, neuronal differentiation and survival.PurposeRecently, BDNF depletion is reported in neurodegenerative as well as in psychiatric disorders, associated with severity of neurological dysfunction. Role of BDNF as a biomarker in ASD is gaining significance. Pre-clinical results have linked BDNF depletion in autism and mental retardation, however, with conflicting findings.MethodsIn view of this, a preliminary study was carried out to measure serum BDNF levels in 48 children with ASD and mental retardation, and 29 age-matched controls.ResultsSerum BDNF levels were found significantly higher (p<0.001) in atypical autistic subjects (clinically milder phenotype) as compared to controls, but not in typical ASD cases (clinically severe phenotype). BDNF levels were significantly lower in females with typical/Rett Syndrome (p<0.05), but not in males with typical autism (p>0.1), as compared to controls. Lower BDNF levels indicate impairment in neuroprotective mechanism, while higher levels may imply a manifested protective response.ConclusionOur study highlights the differential BDNF response based on the severity of neurobehavioral deficit, indicating a possible neuroprotective role of this molecule and supporting its exploration in targeted therapy in ASD.

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“…Indeed, mice with a less severe Mecp2 mutation, such as a mutation that results in a truncated protein instead of null mutation, could live even longer (Shahbazian et al, 2002). Recent case studies have shown that male patient survivors with RTT-like phenotypes do not carry pathogenic mutations in the MECP2 gene (Santos et al, 2009). Conversely, there is evidence that MECP2 null mutations in males may be responsible for a wide spectrum of neurological disorders that are distinctly different from RTT (Villard, 2007).…”

Section: Introductionmentioning

confidence: 99%

Habituation without NMDA Receptor-Dependent Desensitization of Hering–Breuer Apnea Reflex in a Mecp2+/− Mutant Mouse Model of Rett Syndrome

Song¹,

Tin²,

Giacometti³

et al. 2011

Front. Integr. Neurosci.

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Non-associative learning is a basic neuroadaptive behavior exhibited in almost all animal species and sensory modalities but its functions and mechanisms in the mammalian brain are poorly understood. Previous studies have identified two distinct forms of non-associative learning in the classic Hering–Breuer inflation reflex (HBIR) induced apnea in rats: NMDA receptor (NMDAR)-independent habituation in a primary vagal pathway and NMDAR-dependent desensitization in a secondary pontine pathway. Here, we show that abnormal non-associative learning of the HBIR may underlie the endophenotypic tachypnea in an animal model of Rett syndrome (RTT), an autism-spectrum disorder caused by mutations in the X-linked gene encoding methyl-CpG-binding protein 2 (MECP2). Mecp2+/− symptomatic mice on a mixed-strain background demonstrated significantly increased resting respiratory frequency with shortened expiration and normal inspiratory duration compared with asymptomatic mutants and wild-type controls, a phenotype that is characteristic of girls with RTT. Low-intensity electrical stimulation of the vagus nerve elicited fictive HBIR with time-dependent habituation in both Mecp2+/− and wild-type mice. However, time-dependent desensitization of the HBIR was evidenced only in wild-type controls and asymptomatic mutant mice but was absent or suppressed in Mecp2+/− symptomatic mice or in wild-type mice after blockade of NMDAR with dizocilpine. Remarkably, ∼50% of the Mecp2+/− mice developed these X-linked phenotypes despite somatic mosaicism. Such RTT-like respiratory endophenotypes in mixed-strain Mecp2+/− mice differed from those previously reported in Mecp2-/y mice on pure C57BL/6J background. These findings provide the first evidence indicating that impaired NMDAR-dependent desensitization of the HBIR may contribute to the endophenotypic tachypnea in RTT.

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Mutations in the MECP2 Gene Are Not a Major Cause of Rett Syndrome-Like or Related Neurodevelopmental Phenotype in Male Patients

Cited by 12 publications

References 44 publications

DIA1R Is an X-Linked Gene Related to Deleted In Autism-1

DIA1R Is an X-Linked Gene Related to Deleted In Autism-1

Brain-Derived Neurotrophic Factor in children with Autism Spectrum Disorder

Habituation without NMDA Receptor-Dependent Desensitization of Hering–Breuer Apnea Reflex in a Mecp2+/− Mutant Mouse Model of Rett Syndrome

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