Xq26.2-q26.3 microduplication in two brothers with intellectual disabilities: clinical and molecular characterization

Madrigal, Irene; Fernández‐Burriel, Miguel; Rodríguez‐Revenga, Laia; Cabrera, José Carlos; Martí, M; Mur, Antonio; Milá, Montserrat

doi:10.1038/jhg.2010.119

Cited by 13 publications

(16 citation statements)

References 38 publications

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“…Second, the finding that patients with other conditions had different duplications within the same region narrowed our focus to the smallest region of overlap. A duplication encompassing CD40LG and ARHGEF6 but not RBMX and GPR101 occurred in a family with low birth weight, intellectual disability, and craniofacial abnormalities, 16 which suggests that duplications with the exclusion of RBMX and GPR101 do not lead to gigantism. Third, short stature has been reported in several patients with deletions in this region, which suggests that the absence of these genes may lead to the opposite phenotype (Table S4 in the Supplementary Appendix).…”

Section: Discussionmentioning

confidence: 98%

“…Third, short stature has been reported in several patients with deletions in this region, which suggests that the absence of these genes may lead to the opposite phenotype (Table S4 in the Supplementary Appendix). 16–18 Other investigators have described at least 15 additional patients with the same phenotype of early-onset growth who may be good candidates for a diagnosis of X-LAG (Table S3 in the Supplementary Appendix). …”

Section: Discussionmentioning

confidence: 99%

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Gigantism and Acromegaly Due to Xq26 Microduplications and GPR101 Mutation

Trivellin¹,

Daly²,

Faucz³

et al. 2014

N Engl J Med

293

378

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BACKGROUND Increased secretion of growth hormone leads to gigantism in children and acromegaly in adults; the genetic causes of gigantism and acromegaly are poorly understood. METHODS We performed clinical and genetic studies of samples obtained from 43 patients with gigantism and then sequenced an implicated gene in samples from 248 patients with acromegaly. RESULTS We observed microduplication on chromosome Xq26.3 in samples from 13 patients with gigantism; of these samples, 4 were obtained from members of two unrelated kindreds, and 9 were from patients with sporadic cases. All the patients had disease onset during early childhood. Of the patients with gigantism who did not carry an Xq26.3 microduplication, none presented before the age of 5 years. Genomic characterization of the Xq26.3 region suggests that the microduplications are generated during chromosome replication and that they contain four protein-coding genes. Only one of these genes, GPR101, which encodes a G-protein–coupled receptor, was overexpressed in patients’ pituitary lesions. We identified a recurrent GPR101 mutation (p.E308D) in 11 of 248 patients with acromegaly, with the mutation found mostly in tumors. When the mutation was transfected into rat GH3 cells, it led to increased release of growth hormone and proliferation of growth hormone–producing cells. CONCLUSIONS We describe a pediatric disorder (which we have termed X-linked acrogigantism [X-LAG]) that is caused by an Xq26.3 genomic duplication and is characterized by early-onset gigantism resulting from an excess of growth hormone. Duplication of GPR101 probably causes X-LAG. We also found a recurrent mutation in GPR101 in some adults with acromegaly. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development and others.)

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Gigantism and Acromegaly Due to Xq26 Microduplications and GPR101 Mutation

Trivellin¹,

Daly²,

Faucz³

et al. 2014

N Engl J Med

293

378

View full text Add to dashboard Cite

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“…Recent studies have linked mutations in human NHE6/SLC9A6 to pronounced cognitive and developmental impairments characterized by severe intellectual disability, autistic behavior, epilepsy, ataxia, and features closely resembling Angelman and Christianson syndromes (Gilfillan et al, 2008;Garbern et al, 2010;Madrigal et al, 2010;Tzschach et al, 2011). Mice containing a null mutation of NHE6 also display a neurodegenerative phenotype, though less dramatic (Strømme et al, 2011).…”

Section: Discussionmentioning

confidence: 99%

Enhanced Recruitment of Endosomal Na⁺/H⁺Exchanger NHE6 into Dendritic Spines of Hippocampal Pyramidal Neurons during NMDA Receptor-Dependent Long-Term Potentiation

Deane

Ilie

Sizdahkhani³

et al. 2013

J. Neurosci.

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Postsynaptic endosomal trafficking has emerged as a principal regulatory mechanism of structural and functional plasticity of glutamatergic synapses. Recycling endosomes perform activity-dependent transport of AMPA receptors (AMPARs) and lipids to the postsynaptic membrane, activities that are known to contribute to long-term synaptic potentiation and hypothesized to subserve learning and memory processes in the brain. Recently, genetic defects in a widely expressed vesicular pH-regulating transporter, the Na ϩ /H ϩ exchanger NHE6 isoform, have been implicated in neurodevelopmental disorders including severe X-linked mental retardation and autism. However, little information is available regarding the cellular properties of this transporter in the CNS. Here, we show by quantitative light microscopy that the protein abundance of NHE6 is developmentally regulated in area CA1 of the mouse hippocampus. Within pyramidal neurons, NHE6 was found to localize to discrete puncta throughout the soma and neurites, with noticeable accumulation at dendritic spines and presynaptic terminals. Dual immunolabeling of dendritic spines revealed that NHE6 partially colocalizes with typical markers of early and recycling endosomes as well as with the AMPAR subunit GluA1. Significantly, NHE6-containing vesicles exhibited enhanced translocation to dendritic spine heads during NMDA receptor (NMDAR)-dependent long-term potentiation. These data suggest that NHE6 may play a unique, previously unrecognized, role at glutamatergic synapses that are important for learning and memory.

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“…In addition, to gene deletions and mutations, microduplications in Xq26.2-q26.3 involving NHE6 have been reported in patients with intellectual disability, short stature, microcephaly, and hypopituitarism (Madrigal et al, 2010). Similar clinical presentations have been described with MECP2 mutations, wherein both loss of function mutations and increased gene dosage resulting from gene duplications are associated with prominent neurological phenotypes including intellectual disability (Chahrour et al, 2008; Peters et al, 2013).…”

Section: Patient Mutations In Enhe: Clinical Featuresmentioning

confidence: 99%

An inside job: how endosomal Na+/H+ exchangers link to autism and neurological disease

Kondapalli¹,

Prasad²,

Rao³

2014

Front. Cell. Neurosci.

109

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Autism imposes a major impediment to childhood development and a huge emotional and financial burden on society. In recent years, there has been rapidly accumulating genetic evidence that links the eNHE, a subset of Na+/H+ exchangers that localize to intracellular vesicles, to a variety of neurological conditions including autism, attention deficit hyperactivity disorder (ADHD), intellectual disability, and epilepsy. By providing a leak pathway for protons pumped by the V-ATPase, eNHE determine luminal pH and regulate cation (Na+, K+) content in early and recycling endosomal compartments. Loss-of-function mutations in eNHE cause hyperacidification of endosomal lumen, as a result of imbalance in pump and leak pathways. Two isoforms, NHE6 and NHE9 are highly expressed in brain, including hippocampus and cortex. Here, we summarize evidence for the importance of luminal cation content and pH on processing, delivery and fate of cargo. Drawing upon insights from model organisms and mammalian cells we show how eNHE affect surface expression and function of membrane receptors and neurotransmitter transporters. These studies lead to cellular models of eNHE activity in pre- and post-synaptic neurons and astrocytes, where they could impact synapse development and plasticity. The study of eNHE has provided new insight on the mechanism of autism and other debilitating neurological disorders and opened up new possibilities for therapeutic intervention.

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Xq26.2-q26.3 microduplication in two brothers with intellectual disabilities: clinical and molecular characterization

Cited by 13 publications

References 38 publications

Gigantism and Acromegaly Due to Xq26 Microduplications and GPR101 Mutation

Gigantism and Acromegaly Due to Xq26 Microduplications and GPR101 Mutation

Enhanced Recruitment of Endosomal Na⁺/H⁺Exchanger NHE6 into Dendritic Spines of Hippocampal Pyramidal Neurons during NMDA Receptor-Dependent Long-Term Potentiation

An inside job: how endosomal Na+/H+ exchangers link to autism and neurological disease

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Xq26.2-q26.3 microduplication in two brothers with intellectual disabilities: clinical and molecular characterization

Cited by 13 publications

References 38 publications

Gigantism and Acromegaly Due to Xq26 Microduplications and GPR101 Mutation

Gigantism and Acromegaly Due to Xq26 Microduplications and GPR101 Mutation

Enhanced Recruitment of Endosomal Na+/H+Exchanger NHE6 into Dendritic Spines of Hippocampal Pyramidal Neurons during NMDA Receptor-Dependent Long-Term Potentiation

An inside job: how endosomal Na+/H+ exchangers link to autism and neurological disease

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Enhanced Recruitment of Endosomal Na⁺/H⁺Exchanger NHE6 into Dendritic Spines of Hippocampal Pyramidal Neurons during NMDA Receptor-Dependent Long-Term Potentiation