Sporadic Heterozygous Frameshift Mutation ofHESX1Causing 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.

Transcriptome analysis reveals determinant stages controlling human embryonic stem cell commitment to neuronal cells

“…In humans, various mutations of the SIX3 gene, mapped to 2q21, are associated with holoprosencephaly (56 -60) and schizophrenia (61). Different mutations of the HESX1 gene, mapped to 3p14.3, are related to septooptic dysplasia (62)(63)(64)(65) and pituitary deficiency (63, 66 -68). In addition, the expression of Six3 and Hesx1 genes is highly enriched in the prospective E7.0 mouse anterior ectoderm (29), where the prospective neural epithelium originates, suggesting that SIX3 and HESX1 may play a crucial role in human neural commitment as well.…”

Optic nerve axons: life and death before birth

“…Abnormalities of a number of genes 75,76 and axon guidance proteins 77 may result in abnormalities of chiasmal development.…”

“…166 Family history and genetics: Familial cases have been described, 12,167-171 but they are rare and not all necessarily genetic, and in the absence of a recurrent environmental cause (such as drugs or alcohol) a very low recurrence risk can be given. Associations with gene mutations, especially of HESX1, are recorded: 75,76,79,172 some of these have been in siblings, and especially if associated with consanguinity, or if two siblings are affected, the condition may be inherited as an autosomal recessive trait. Optic disc hypoplasia, and its systemic associations should, however, mostly be regarded as sporadic in their occurrence.…”

Molecular analysis of PROP1, PIT1, HESX1, LHX3, and LHX4 shows high frequency of PROP1 mutations in patients with familial forms of combined pituitary hormone deficiency

“…HESX1 mutations may be associated with EPP or NPPP (5,(20)(21)(22). With regard to the image of the anterior pituitary, the majority of the patients with PTF mutations have a hypoplastic or normal anterior pituitary gland, but an enlarged pituitary mass resembling hyperplasia of the adenohypophysis may be detected less frequently in some patients with PROP1 mutations.…”