期刊
BRAIN
卷 136, 期 -, 页码 3096-3105出版社
OXFORD UNIV PRESS
DOI: 10.1093/brain/awt218
关键词
hypothalamus; congenital blindness; brain development; molecular genetics; malformations of cortical development
资金
- Child Growth Foundation
- Novo Nordisk Ltd
- Ulverscroft Foundation
- NIHR Specialist Paediatric Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust
- UCL Institute of Child Health the Medical Research Council UK [G0700089]
- Wellcome Trust [GR082557]
- Great Ormond St Hospital Children's Charity
- Great Ormond Street Hospital (GOSH) Biomedical Research Centre (BRC) of the National Institute for Health Research (NIHR)
- Joint MRC [G0700089]
- Human Developmental Biology Resource
- MRC [MC_PC_15004, G0700089] Funding Source: UKRI
- Great Ormond Street Hospital Childrens Charity [V1255, V1257, W1055] Funding Source: researchfish
- Medical Research Council [G0700089, MC_PC_15004] Funding Source: researchfish
- Rosetrees Trust [M257] Funding Source: researchfish
We describe a previously unreported syndrome characterized by secondary (post-natal) microcephaly with fronto-temporal lobe hypoplasia, multiple pituitary hormone deficiency, seizures, severe visual impairment and abnormalities of the kidneys and urinary tract in a highly consanguineous family with six affected children. Homozygosity mapping and exome sequencing revealed a novel homozygous frameshift mutation in the basic helix-loop-helix transcription factor gene ARNT2 (c.1373_1374dupTC) in affected individuals. This mutation results in absence of detectable levels of ARNT2 transcript and protein from patient fibroblasts compared with controls, consistent with nonsense-mediated decay of the mutant transcript and loss of ARNT2 function. We also show expression of ARNT2 within the central nervous system, including the hypothalamus, as well as the renal tract during human embryonic development. The progressive neurological abnormalities, congenital hypopituitarism and post-retinal visual pathway dysfunction in affected individuals demonstrates for the first time the essential role of ARNT2 in the development of the hypothalamo-pituitary axis, post-natal brain growth, and visual and renal function in humans.
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