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

作者：Webb Emma A; AlMutair Angham; Kelberman Daniel; Bacchelli Chiara; Chanudet Estelle; Lescai Francesco; Andoniadou Cynthia L; Banyan Abdul; Alsawaid Al; Alrifai Muhammad T; Alahmesh Mohammed A; Balwi M; Mousavy Gharavy Seyedeh N; Lukovic Biljana; Burke Derek; McCabe Mark J; Kasia Tessa; Kleta Robert; Stupka Elia; Beales Philip L; Thompson Dorothy A; Chong W Kling; Alkuraya Fowzan S; Martinez Barbera Juan Pedro; Sowden Jane C; Dattani Mehul T^*

来源：Brain, 2013, 136(10): 3096-3105.

DOI：10.1093/brain/awt218

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

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.

• 出版日期2013-10