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

Area of Science:

• Genetics
• Developmental Biology
• Neurology

Background:

• A consanguineous family presented with a rare syndrome affecting six children.
• The syndrome included secondary microcephaly, pituitary hormone deficiency, seizures, visual impairment, and renal abnormalities.

Purpose of the Study:

• To identify the genetic cause of the newly reported syndrome.
• To elucidate the role of the ARNT2 gene in human development and disease.

Main Methods:

• Homozygosity mapping and exome sequencing were employed.
• ARNT2 transcript and protein levels were analyzed in patient fibroblasts.
• ARNT2 expression during human embryonic development was examined.

Main Results:

• A novel homozygous frameshift mutation (c.1373_1374dupTC) in the ARNT2 gene was identified in affected individuals.
• The mutation led to a loss of ARNT2 function, with undetectable transcript and protein levels.
• ARNT2 expression was observed in the central nervous system and renal tract during development.

Conclusions:

• The identified ARNT2 mutation is responsible for the described syndrome.
• This study demonstrates the critical role of ARNT2 in the development of the hypothalamo-pituitary axis, brain growth, vision, and kidney function.
• Loss of ARNT2 function results in progressive neurological and developmental abnormalities.