Screening copy number variations by array comparative genomic hybridization in 30 patients with congenital hypopituitarism.

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Objective : Mutations in transcription factors genes, which are regulated spatially and temporally in the pituitary gland, result in congenital hypopituitarism(CH) in humans. The prevalence of CH attributable to known transcription factor mutations appears to be rare and other causative genes for CH would remain to be identified. Due to the sporadic occurrence of CH, de novo chromosomal rearrangements are conceivably representing one of the molecular mechanisms participating in its etiology, especially in syndromic CH.Subjects and Methods : We enrolled 88(Syndromic : 30, Non-syndromic 58) Japanese CH patients. We performed an array CGH screen of 30 syndromic CH patients to determine the role of copy number variations(CNVs) in the etiology of the disease.Results : We identified one heterozygous 350kb deletion of PAX6 enhancer region in one patient showing isolated GH deficiency, cleft palate, and optic disc cupping. For all patients, we analyzed all coding exons and flanking introns ofPAX6 and identified a novel mutation, namely p. N116S in one non-syndromic CH patient showing isolated GH deficiency. In vitro experiments showed that N116S PAX6 mutation was associated with an impairment of the transactivation capacities of PAX6 binding element, without any dominant-negative effects.Conclusions : PAX6 is a well-known regulator of eye development, and its heterozygous mutations in humans cause congenital eye anomalies such as aniridia. This study showed, for the first time, that heterozygous PAX6 mutations are associated with CH patients with or without ocular malformation.