title: Sporadic heterozygous frameshift mutation of HESX1 causing pituitary and optic nerve hypoplasia and combined pituitary hormone deficiency in a Japanese patient.
abstract: HESX1/Hesx1 is a member of the paired-like class of homeobox genes and is essential for pituitary and forebrain development. Mice with a targeted homozygous deletion of the Hesx1 show severe central nervous system defects, absence of optic vesicles, and a very small anterior pituitary gland. This phenotype is similar to the abnormalities observed in the human disorder called septo-optic dysplasia, a syndromic form of congenital hypopituitarism. To date, four missense mutations in the human HESX1 have been described in individuals with phenotypes ranging from severe septo-optic dysplasia, relatively mild combined pituitary hormone deficiency (CPHD), to isolated GH deficiency. Here we report a Japanese patient with CPHD (GH, TSH, LH, FSH, and ACTH deficiency) due to a novel sporadic HESX1 mutation. Brain magnetic resonance imaging examination revealed hypoplastic anterior pituitary, ectopic posterior lobe, and left optic nerve hypoplasia. Molecular analysis identified the insertion of a heterozygous mutation (306/307ins AG) in the exon 2 of the HESX1. This mutation changes a reading frame and introduces a premature stop codon soon after the mutation site. Therefore, this mutation would be predicted to generate a protein lacking the carboxyl-terminal homebox domain (DNA-binding domain) and cause the disease. Family analysis demonstrated that neither of the patient's parents harbored this mutation, indicating that the mutation had arisen de novo. In conclusion, a de novo heterozygous frameshift mutation in exon 2 of the HESX1 causes severe CPHD with optic nerve hypoplasia in a human.
authors.affiliation: Department of Pediatrics, Hokkaido University School of Medicine, Sapporo 060-0835, Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Tajima
authors.forename: Tsukasa
authors.initials: T
authors.lastname: Hattorri
authors.forename: Takeo
authors.initials: T
authors.lastname: Nakajima
authors.forename: Kouji
authors.initials: K
authors.lastname: Okuhara
authors.forename: Kohei
authors.initials: K
authors.lastname: Sato
authors.forename: Shuji
authors.initials: S
authors.lastname: Abe
authors.forename: Jun
authors.initials: J
authors.lastname: Nakae
authors.forename: Kenji
authors.initials: K
authors.lastname: Fujieda
mesh_terms: D044466:Asian People / Q000235:genetics*; D001483:Base Sequence / Q000235:genetics; D051792:Basic Helix-Loop-Helix Proteins; D002675:Child, Preschool; D016368:Frameshift Mutation; D006579:Heterozygote; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007564:Japan; D008297:Male; D008661:Metabolism, Inborn Errors / Q000235:genetics; D009900:Optic Nerve / Q000002:abnormalities*; D010902:Pituitary Gland / Q000002:abnormalities*; D010907:Pituitary Hormones / Q000172:deficiency*; D000072056:Transcription Factor HES-1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D018398:Homeodomain Proteins; D010907:Pituitary Hormones; D000072056:Transcription Factor HES-1; C489736:HESX1 protein, human; C078493:HES1 protein, human