| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
Submitted on July 25, 2006
Accepted on November 21, 2006
Biochemistry, Endocrinology and Metabolism Unit, Institute of Child Health, London, UK; Université Paris-Descartes; AP-HP, Hôpital Bicêtre, 94275 Le Kremlin Bicêtre, France; Third Department of Pediatrics, University of Athens School of Medicine, Athens, Greece; Hospital for Children and Adolescents, University of Leipzig, Leipzig, Germany; Charite, Institute of Experimental Pediatric Endocrinology, Augustenburgerplatz 1, D-13353, Berlin; Department of Endocrinology, Christie Hospital NHS Trust, Manchester, UK
* To whom correspondence should be addressed. E-mail: m.dattani{at}ich.ucl.ac.uk.
Context: Mutations in the transcription factor HESX1 have previously been described in association with septo-optic dysplasia (SOD) as well as isolated defects of the hypothalamic-pituitary axis. Objective: Given that previous screening was carried out by SSCP detection alone and limited to coding regions, we performed an in-depth genetic analysis of HESX1 to establish the true contribution of HESX1 genetic defects to the etiology of hypopituitarism. Design: 724 non-familial patients with either SOD (n = 314) or isolated pituitary dysfunction, optic nerve hypoplasia (ONH) or midline neurological abnormalities (n = 410) originally screened by SSCP were re-screened by heteroduplex detection for mutations in the coding and regulatory regions of HESX1. In addition, direct sequencing of HESX1 was performed in 126 patients with familial hypopituitarism from 66 unrelated families, and in 11 patients born to consanguineous parents. Patients: All patients studied had at least 1 of the 3 classical features associated with SOD (ONH, hypopituitarism, midline forebrain defects). Results: Novel sequence changes identified included a functionally significant heterozygous mutation at a highly conserved residue (E149K) in a patient with isolated growth hormone deficiency and digital abnormalities. The overall incidence of coding region mutations within the cohort was less than 1%. Conclusions: Mutations within HESX1 are a rare cause of SOD and hypopituitarism. However, the large number of familial patients with SOD in whom no mutations were identified is suggestive of an etiological role for other genetic factors. Furthermore, we have found that within our cohort SOD is associated with a reduced maternal age compared with isolated defects of the hypothalamo-pituitary axis.
This article has been cited by other articles:
 |
|
 |
|
  E. Sajedi, C. Gaston-Massuet, M. Signore, C. L. Andoniadou, D. Kelberman, S. Castro, H. C. Etchevers, D. Gerrelli, M. T. Dattani, and J. P. Martinez-Barbera Analysis of mouse models carrying the I26T and R160C substitutions in the transcriptional repressor HESX1 as models for septo-optic dysplasia and hypopituitarism Dis. Model. Mech., November 1, 2008; 1(4-5): 241 - 254. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Dateki, M. Fukami, N. Sato, K. Muroya, M. Adachi, and T. Ogata OTX2 Mutation in a Patient with Anophthalmia, Short Stature, and Partial Growth Hormone Deficiency: Functional Studies Using the IRBP, HESX1, and POU1F1 Promoters J. Clin. Endocrinol. Metab., October 1, 2008; 93(10): 3697 - 3702. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Kelberman and M. T. Dattani Hypothalamic and pituitary development: novel insights into the aetiology Eur. J. Endocrinol., August 1, 2007; 157(suppl_1): S3 - S14. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
