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Small 6q16.1 Deletions Encompassing POU3F2 Cause Susceptibility to Obesity and Variable Developmental Delay with Intellectual Disability.

ABSTRACT: Genetic studies of intellectual disability and identification of monogenic causes of obesity in humans have made immense contribution toward the understanding of the brain and control of body mass. The leptin > melanocortin > SIM1 pathway is dysregulated in multiple monogenic human obesity syndromes but its downstream targets are still unknown. In ten individuals from six families, with overlapping 6q16.1 deletions, we describe a disorder of variable developmental delay, intellectual disability, and susceptibility to obesity and hyperphagia. The 6q16.1 deletions segregated with the phenotype in multiplex families and were shown to be de novo in four families, and there was dramatic phenotypic overlap among affected individuals who were independently ascertained without bias from clinical features. Analysis of the deletions revealed a ?350 kb critical region on chromosome 6q16.1 that encompasses a gene for proneuronal transcription factor POU3F2, which is important for hypothalamic development and function. Using morpholino and mutant zebrafish models, we show that POU3F2 lies downstream of SIM1 and controls oxytocin expression in the hypothalamic neuroendocrine preoptic area. We show that this finding is consistent with the expression patterns of POU3F2 and related genes in the human brain. Our work helps to further delineate the neuro-endocrine control of energy balance/body mass and demonstrates that this molecular pathway is conserved across multiple species.

SUBMITTER: Kasher PR

PROVIDER: S-EPMC4746363 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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Small 6q16.1 Deletions Encompassing POU3F2 Cause Susceptibility to Obesity and Variable Developmental Delay with Intellectual Disability.

Kasher Paul R PR Schertz Katherine E KE Thomas Megan M Jackson Adam A Annunziata Silvia S Ballesta-Martinez María J MJ Campeau Philippe M PM Clayton Peter E PE Eaton Jennifer L JL Granata Tiziana T Guillén-Navarro Encarna E Hernando Cristina C Laverriere Caroline E CE Liedén Agne A Villa-Marcos Olaya O McEntagart Meriel M Nordgren Ann A Pantaleoni Chiara C Pebrel-Richard Céline C Sarret Catherine C Sciacca Francesca L FL Wright Ronnie R Kerr Bronwyn B Glasgow Eric E Banka Siddharth S

American journal of human genetics 20160128 2

Genetic studies of intellectual disability and identification of monogenic causes of obesity in humans have made immense contribution toward the understanding of the brain and control of body mass. The leptin > melanocortin > SIM1 pathway is dysregulated in multiple monogenic human obesity syndromes but its downstream targets are still unknown. In ten individuals from six families, with overlapping 6q16.1 deletions, we describe a disorder of variable developmental delay, intellectual disability, ...[more]

PMID: 26833329

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Project description:We aimed to define a novel autosomal recessive neurodevelopmental disorder, characterize its clinical features, and identify the underlying genetic cause for this condition. Clinical and genetic data from affected individuals with neurological disorders were matched across families from five global sites. Here, we report five recessive CSPG4 (NM_001897) missense variants [three homozygous: c.A1370G (p.Asp457Gly), c.2627G>A (p.Arg876His) and c.3247C>A (p.Gln1083Lys), and two compound heterozygote: c.A1370G and c.5156A>G (p.Asp457Gly and p.Gln1719Arg) and c.658A>G and c.1220_1221delinsTG (p.(Thr220Ala and p.Pro407Leu)] by next-generation sequencing of five unrelated families with seven affected subjects. All subjects share a novel neurodevelopmental syndrome characterized by severe intellectual disability, global developmental delay, delayed ability to walk, speech and language delay, distinctive facial features, along with varying degrees of neurological impairment, including hypotonia, cerebellar hypoplasia, and/or seizures. All CSPG4 variants were predicted to be damaging using in silico tools, and three-dimensional molecular modeling suggested significant alterations in protein stability, compromising inter- and intra-molecular interactions. The impact on neurological and craniofacial development was analyzed in CRISPR/Cas9-mediated zebrafish models. CSPG4 variants affected notochord development, neuronal function, and cerebellar structure along with a disorganized head scaffold with anomalous skeletal and cartilage components. Two individuals metabolomics and crispant transcriptomics revealed significant perturbation of metabolites, extracellular matrix (ECM) regulating pathways, and genes previously described to cause mental retardation, dwarfism, and facial anomalies in humans. Our study links novel, rare, damaging variants of the ECM gene CSPG4 to a novel recessive Mendelian neurodevelopmental disorder in humans and supports the role of CSPG4 in early development.

Dataset Information

Small 6q16.1 Deletions Encompassing POU3F2 Cause Susceptibility to Obesity and Variable Developmental Delay with Intellectual Disability.

Publications

Small 6q16.1 Deletions Encompassing POU3F2 Cause Susceptibility to Obesity and Variable Developmental Delay with Intellectual Disability.

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