title: ARNT2 mutation causes hypopituitarism, post-natal microcephaly, visual and renal anomalies.
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.
authors.affiliation: 1 Developmental Endocrinology Research Group, UCL Institute of Child Health and Department of Endocrinology, Great Ormond Street Hospital for Children, London, WC1N 1EH, UK.
authors.forename: Emma A
authors.initials: EA
authors.lastname: Webb
authors.forename: Angham
authors.initials: A
authors.lastname: AlMutair
authors.forename: Daniel
authors.initials: D
authors.lastname: Kelberman
authors.forename: Chiara
authors.initials: C
authors.lastname: Bacchelli
authors.forename: Estelle
authors.initials: E
authors.lastname: Chanudet
authors.forename: Francesco
authors.initials: F
authors.lastname: Lescai
authors.forename: Cynthia L
authors.initials: CL
authors.lastname: Andoniadou
authors.forename: Abdul
authors.initials: A
authors.lastname: Banyan
authors.forename: Al
authors.initials: A
authors.lastname: Alsawaid
authors.forename: Muhammad T
authors.initials: MT
authors.lastname: Alrifai
authors.forename: Mohammed A
authors.initials: MA
authors.lastname: Alahmesh
authors.forename: M
authors.initials: M
authors.lastname: Balwi
authors.forename: Seyedeh N
authors.initials: SN
authors.lastname: Mousavy-Gharavy
authors.forename: Biljana
authors.initials: B
authors.lastname: Lukovic
authors.forename: Derek
authors.initials: D
authors.lastname: Burke
authors.forename: Mark J
authors.initials: MJ
authors.lastname: McCabe
authors.forename: Tessa
authors.initials: T
authors.lastname: Kasia
authors.forename: Robert
authors.initials: R
authors.lastname: Kleta
authors.forename: Elia
authors.initials: E
authors.lastname: Stupka
authors.forename: Philip L
authors.initials: PL
authors.lastname: Beales
authors.forename: Dorothy A
authors.initials: DA
authors.lastname: Thompson
authors.forename: W Kling
authors.initials: WK
authors.lastname: Chong
authors.forename: Fowzan S
authors.initials: FS
authors.lastname: Alkuraya
authors.forename: Juan-Pedro
authors.initials: JP
authors.lastname: Martinez-Barbera
authors.forename: Jane C
authors.initials: JC
authors.lastname: Sowden
authors.forename: Mehul T
authors.initials: MT
authors.lastname: Dattani
mesh_terms: D051784:Aryl Hydrocarbon Receptor Nuclear Translocator / Q000235:genetics*; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007018:Hypopituitarism / Q000175:diagnosis / Q000235:genetics*; D007031:Hypothalamus / Q000378:metabolism; D007668:Kidney / Q000002:abnormalities* / Q000378:metabolism; D008297:Male; D008831:Microcephaly / Q000175:diagnosis / Q000235:genetics*; D009154:Mutation / Q000235:genetics*; D010907:Pituitary Hormones / Q000235:genetics / Q000378:metabolism*; D013577:Syndrome; D014157:Transcription Factors; D014796:Visual Perception
chemical_list: D051784:Aryl Hydrocarbon Receptor Nuclear Translocator; D051792:Basic Helix-Loop-Helix Proteins; D010907:Pituitary Hormones; D014157:Transcription Factors; C490989:ARNT2 protein, human
keywords: brain development; congenital blindness; hypothalamus; malformations of cortical development; molecular genetics
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