© J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart · New York
A Novel Mutation (V101A) of the LHX4 Gene in a Japanese Patient with Combined Pituitary Hormone Deficiency
first decision 15.05.2009
23. Oktober 2009 (eFirst)
Objective: LHX4, a LIM-homeodomain transcription factor, is required for development of the pituitary and nervous system. Several mutations of the LHX4 gene have been identified in patients with combined pituitary hormone deficiency (CPHD). The objective of the study was to clarify the molecular basis of a Japanese patient of CPHD with a small anterior pituitary and an ectopic posterior pituitary.
Methods: Genomic DNA was extracted from blood samples of the patient. Exons and exon-intron junctions of the LHX4 gene were amplified and sequenced. An expression vector of the mutant LHX4 protein was constructed and its function was analyzed in vitro.
Results: A novel missense mutation (V101A) was identified. In vitro transfection studies demonstrated that V101A mutant LHX4 was unable to activate the POU1F1 and FSHβ subunit gene promoter, indicating a loss of function mutation.
Conclusion: Our results identify a novel loss of function mutation of the LHX4 gene in a Japanese patient with CPHD.
LHX4 - LIM domain - combined pituitary hormone deficiency (CPHD)
- 1 Bhangoo AP. et al . Clinical case seminar: a novel LHX3 mutation presenting as combined pituitary hormonal deficiency. J Clin Endocrinol Metab. 2006; 91 747-753
- 2 Castinetti F. et al . A novel dysfunctional LHX4 mutation with high phenotypical variability in patients with hypopituitarism. J Clin Endocrinol Metab. 2008; 93 2790-2799
- 3 Cushman LJ. et al . Genetic defects in the development and function of the anterior pituitary gland. Ann Med. 2002; 34 179-191
- 4 Howard PW, Maurer RA. Identification of a conserved protein that interacts with specific LIM homeodomain transcription factors. J Biol Chem. 2000; 275 13336-13342
- 5 Howard PW, Maurer RA. A point mutation in the LIM domain of LHX3 reduces activation of the glycoprotein hormone alpha subunit promoter. J Biol Chem. 2001; 276 19020-19026
- 6 Kelberman D, Dattani MT. The role of transcription factors implicated in anterior pituitary development in the aetiology of congenital hypopituitarism. Ann Med. 2006; 38 560-577
- 7 Machinis K. et al . Syndromic short stature in patients with a germline mutation in the LIM homeobox LHX4. Am J Hum Genet. 2001; 69 961-968
- 8 Machinis K, Amselem S. Functional relationship between LHX4 and POU1F1 in light of the LHX4 mutation identified in patients with pituitary defects. J Clin Endocrinol Metab. 2005; 90 5456-5462
- 9 Mullen RD. et al . Roles of the LHX3 and LHX4 LIM-homeodomain factors in pituitary development. Mol Cell Endocrinol. 2007; 265 190-195
- 10 Netchine I. et al . Mutations in LHX3 result in a new syndrome revealed by combined pituitary hormone deficiency. Nat Genet. 2000; 5 182-186
- 11 Osorio MG. et al . Combined pituitary hormone deficiency caused by a novel mutation of a highly conserved residue (F88S) in the homeodomain of PROP-1. J Clin Endocrinol Metab. 2000; 85 2779-2785
- 12 Pellegrini-Bouiller I. et al . A new mutation of the gene encoding the transcription factor Pit-1 is responsible for combined pituitary hormone deficiency. J Clin Endocrinol Metab. 1996; 81 2790-2796
- 13 Pfaeffle RW. et al . Three novel missense mutations within the LHX4 gene are associated with variable pituitary hormone deficiencies. J Clin Endocrinol Metab. 2008; 93 1062-1071
- 14 Radovick S. et al . A mutation in the POU-homeodomain of Pit-1 responsible for combined pituitary hormone deficiency. Science. 1992; 257 1115-1118
- 15 Raetzman LT. et al . LHX4 and Prop1 are required for cell survival and expansion of the pituitary primordial. Development. 2002; 129 4229-4239
- 16 Riepe FG. et al . Longitudinal imaging reveals pituitary enlargement preceding hypoplasia in two brothers with combined pituitary hormone deficiency attributable to PROP1 mutation. J Clin Endocrinol Metab. 2001; 86 4353-4357
- 17 Sheng HZ. et al . Multistep control of pituitary organogenesis. Science. 1997; 278 1809-1812
- 18 Tajima T. et al . A novel missense mutation (P366 T) of the LHX4 gene causes severe combined pituitary hormone deficiency with pituitary hypoplasia, ectopic posterior lobe and a poorly developed sella turcica. Endocr J. 2007; 54 637-641
- 19 West BE. et al . Regulation of the follicle-stimulating hormone beta gene by the LHX3 LIM-homeodomain transcription factor. Endocrinology. 2004; 145 4866-4879
- 20 Yamashita T. et al . LHX4, a LIM homeobox gene. Genomics. 1997; 44 144-146
T. Tajima, MD, PhD
Department of Pediatrics
Hokkaido University School of Medicine