title: Heterozygous defects in PAX6 gene and congenital hypopituitarism.
abstract: BACKGROUND
  The prevalence of congenital hypopituitarism (CH) attributable to known transcription factor mutations appears to be rare and other causative genes for CH remain to be identified. Due to the sporadic occurrence of CH, de novo chromosomal rearrangements could be one of the molecular mechanisms participating in its etiology, especially in syndromic cases.
  
  
  OBJECTIVE
  To identify the role of copy number variations (CNVs) in the etiology of CH and to identify novel genes implicated in CH.
  
  
  METHODS
  We enrolled 88 (syndromic: 30; non-syndromic: 58) Japanese CH patients. We performed an array comparative genomic hybridization screening in the 30 syndromic CH patients. For all the 88 patients, we analyzed PAX6 by PCR-based sequencing.
  
  
  RESULTS
  We identified one heterozygous 310-kb deletion of the PAX6 enhancer region in one patient showing isolated GH deficiency (IGHD), cleft palate, and optic disc cupping. We also identified one heterozygous 6.5-Mb deletion encompassing OTX2 in a patient with bilateral anophthalmia and multiple pituitary hormone deficiency. We identified a novel PAX6 mutation, namely p.N116S in one non-syndromic CH patient showing IGHD. The p.N116S PAX6 was associated with an impairment of the transactivation capacities of the PAX6-binding elements.
  
  
  CONCLUSIONS
  This study showed that heterozygous PAX6 mutations are associated with CH patients. PAX6 mutations may be associated with diverse clinical features ranging from severely impaired ocular and pituitary development to apparently normal phenotype. Overall, this study identified causative CNVs with a possible role in the etiology of CH in <10% of syndromic CH patients.
authors.affiliation: Department of Endocrinology and MetabolismTokyo Metropolitan Children's Medical Center, Tokyo, JapanDepartment of PediatricsSchool of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, JapanDivision of PediatricsDepartment of Homeostatic Regulation and Development, Graduate School of Medicine and Dental Sciences, Niigata University, Niigata, JapanDepartment of PediatricsSchool of Medicine, Tohoku University, Miyagi, JapanDepartment of Endocrinology and MetabolismKanagawa Children's Medical Center, Yokohama, Japan Department of Endocrinology and MetabolismTokyo Metropolitan Children's Medical Center, Tokyo, JapanDepartment of PediatricsSchool of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, JapanDivision of PediatricsDepartment of Homeostatic Regulation and Development, Graduate School of Medicine and Dental Sciences, Niigata University, Niigata, JapanDepartment of PediatricsSchool of Medicine, Tohoku University, Miyagi, JapanDepartment of Endocrinology and MetabolismKanagawa Children's Medical Center, Yokohama, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Takagi
authors.affiliation: Department of Endocrinology and MetabolismTokyo Metropolitan Children's Medical Center, Tokyo, JapanDepartment of PediatricsSchool of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, JapanDivision of PediatricsDepartment of Homeostatic Regulation and Development, Graduate School of Medicine and Dental Sciences, Niigata University, Niigata, JapanDepartment of PediatricsSchool of Medicine, Tohoku University, Miyagi, JapanDepartment of Endocrinology and MetabolismKanagawa Children's Medical Center, Yokohama, Japan.
authors.forename: Keisuke
authors.initials: K
authors.lastname: Nagasaki
authors.affiliation: Department of Endocrinology and MetabolismTokyo Metropolitan Children's Medical Center, Tokyo, JapanDepartment of PediatricsSchool of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, JapanDivision of PediatricsDepartment of Homeostatic Regulation and Development, Graduate School of Medicine and Dental Sciences, Niigata University, Niigata, JapanDepartment of PediatricsSchool of Medicine, Tohoku University, Miyagi, JapanDepartment of Endocrinology and MetabolismKanagawa Children's Medical Center, Yokohama, Japan.
authors.forename: Ikuma
authors.initials: I
authors.lastname: Fujiwara
authors.affiliation: Department of Endocrinology and MetabolismTokyo Metropolitan Children's Medical Center, Tokyo, JapanDepartment of PediatricsSchool of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, JapanDivision of PediatricsDepartment of Homeostatic Regulation and Development, Graduate School of Medicine and Dental Sciences, Niigata University, Niigata, JapanDepartment of PediatricsSchool of Medicine, Tohoku University, Miyagi, JapanDepartment of Endocrinology and MetabolismKanagawa Children's Medical Center, Yokohama, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Ishii
authors.affiliation: Department of Endocrinology and MetabolismTokyo Metropolitan Children's Medical Center, Tokyo, JapanDepartment of PediatricsSchool of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, JapanDivision of PediatricsDepartment of Homeostatic Regulation and Development, Graduate School of Medicine and Dental Sciences, Niigata University, Niigata, JapanDepartment of PediatricsSchool of Medicine, Tohoku University, Miyagi, JapanDepartment of Endocrinology and MetabolismKanagawa Children's Medical Center, Yokohama, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Amano
authors.affiliation: Department of Endocrinology and MetabolismTokyo Metropolitan Children's Medical Center, Tokyo, JapanDepartment of PediatricsSchool of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, JapanDivision of PediatricsDepartment of Homeostatic Regulation and Development, Graduate School of Medicine and Dental Sciences, Niigata University, Niigata, JapanDepartment of PediatricsSchool of Medicine, Tohoku University, Miyagi, JapanDepartment of Endocrinology and MetabolismKanagawa Children's Medical Center, Yokohama, Japan.
authors.forename: Yumi
authors.initials: Y
authors.lastname: Asakura
authors.affiliation: Department of Endocrinology and MetabolismTokyo Metropolitan Children's Medical Center, Tokyo, JapanDepartment of PediatricsSchool of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, JapanDivision of PediatricsDepartment of Homeostatic Regulation and Development, Graduate School of Medicine and Dental Sciences, Niigata University, Niigata, JapanDepartment of PediatricsSchool of Medicine, Tohoku University, Miyagi, JapanDepartment of Endocrinology and MetabolismKanagawa Children's Medical Center, Yokohama, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Muroya
authors.affiliation: Department of Endocrinology and MetabolismTokyo Metropolitan Children's Medical Center, Tokyo, JapanDepartment of PediatricsSchool of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, JapanDivision of PediatricsDepartment of Homeostatic Regulation and Development, Graduate School of Medicine and Dental Sciences, Niigata University, Niigata, JapanDepartment of PediatricsSchool of Medicine, Tohoku University, Miyagi, JapanDepartment of Endocrinology and MetabolismKanagawa Children's Medical Center, Yokohama, Japan.
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Hasegawa
authors.affiliation: Department of Endocrinology and MetabolismTokyo Metropolitan Children's Medical Center, Tokyo, JapanDepartment of PediatricsSchool of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, JapanDivision of PediatricsDepartment of Homeostatic Regulation and Development, Graduate School of Medicine and Dental Sciences, Niigata University, Niigata, JapanDepartment of PediatricsSchool of Medicine, Tohoku University, Miyagi, JapanDepartment of Endocrinology and MetabolismKanagawa Children's Medical Center, Yokohama, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Adachi
authors.affiliation: Department of Endocrinology and MetabolismTokyo Metropolitan Children's Medical Center, Tokyo, JapanDepartment of PediatricsSchool of Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, JapanDivision of PediatricsDepartment of Homeostatic Regulation and Development, Graduate School of Medicine and Dental Sciences, Niigata University, Niigata, JapanDepartment of PediatricsSchool of Medicine, Tohoku University, Miyagi, JapanDepartment of Endocrinology and MetabolismKanagawa Children's Medical Center, Yokohama, Japan thaseg@a6.keio.jp.
authors.forename: Tomonobu
authors.initials: T
authors.lastname: Hasegawa
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D003460:Crystallization; D005136:Eye Proteins / Q000235:genetics*; D005260:Female; D006579:Heterozygote; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007018:Hypopituitarism / Q000175:diagnosis* / Q000235:genetics*; D008297:Male; D000071841:PAX6 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics*; D010375:Pedigree; D012097:Repressor Proteins / Q000235:genetics*; D055815:Young Adult
chemical_list: D005136:Eye Proteins; D018398:Homeodomain Proteins; D000071841:PAX6 Transcription Factor; C000605730:PAX6 protein, human; D051761:Paired Box Transcription Factors; D012097:Repressor Proteins