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Brain. 2013 Oct;136(Pt 10):3096-105. doi: 10.1093/brain/awt218. Epub 2013 Sep 10.

ARNT2 mutation causes hypopituitarism, post-natal microcephaly, visual and renal anomalies.

Author information

1
1 Developmental Endocrinology Research Group, UCL Institute of Child Health and Department of Endocrinology, Great Ormond Street Hospital for Children, London, WC1N 1EH, UK.

Abstract

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.

KEYWORDS:

brain development; congenital blindness; hypothalamus; malformations of cortical development; molecular genetics

PMID:
24022475
PMCID:
PMC3784281
DOI:
10.1093/brain/awt218
[Indexed for MEDLINE]
Free PMC Article

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