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Molecular analysis of LHX3 gene in patients with isolated or combined deficiency of GH

Grant number: 13/00073-8
Support Opportunities:Scholarships in Brazil - Scientific Initiation
Effective date (Start): April 01, 2013
Effective date (End): December 31, 2014
Field of knowledge:Health Sciences - Medicine - Medical Clinics
Principal Investigator:Luciani Renata Silveira de Carvalho
Grantee:Anna Flávia Figueredo Benedetti
Host Institution: Hospital das Clínicas da Faculdade de Medicina da USP (HCFMUSP). Secretaria da Saúde (São Paulo - Estado). São Paulo , SP, Brazil


In humans, the pituitary gland is composed of two parts, the anterior and posterior. The neurohypophysis originates from embryonic neural ectoderm and secretes the hormones oxytocin and ADH. The adenohypophysis is derived from Rathke's pouch, an outgrowth of the oral ectoderm. It contains five types of secretory cells that secrete the hormones GH, PRL, TSH, LH, FSH, and ACTH.The development of hormone-secreting cells of the anterior pituitary gland requires coordinated action of regulatory genes encoding transcription factors leading to specialized gene expression establishing the differentiated character of these cells. Mutations in these genes are associated with pediatric diseases including isolated and/or combined pituitary hormone deficiency (CPHD). Critical transcription factors include HESX1, ISL1, LHX3, LHX4 PAX6, Pit-1 (POU1F1 gene), OTX1, PITX1, PITX2, PROP1, SIX3 and SIX6.LHX3 is part of the subfamily LIM-homeodomain and is located on chromosome 9 at 9q34.3 region. It encodes three different isoforms, which are LHX3a, LHX3b and M2-LHX3, and it is expressed in the embryonic brain, spinal cord and in Rathke's pouch. To date, 12 mutations have been described in homozygous state. Patients present combined pituitary hormone deficiency (CPHD) due to GH, PRL, TSH, LH and FSH hormonal deficiency. Patient harboring LHX3 mutations leading to CPHD can present short stature, metabolic defects, failure to reach puberty. They are also described having limitations in neck rotation, neural hearing loss, association with autism and changes in image suggestive of hyperintense lesion in the adenohypophysis, besides being able to present pituitary hypoplasia, increased or normal pituitary with topic neurohypophysis in all described cases. The aim of this study is to analyze the LHX3 gene in 53 patients with congenital hypopituitarism with eutopic neurohypophysis and in patients with ectopic neurohypophysis necessarily presenting stiffness neck, deafness, autism and / or pituitary lesions suggesting pituitary adenoma. We also intend to screen LHX3 in patients with congenital hypopituitarism with previous molecular diagnosis, in heterozygous state, in other genes involved in pituitary embryogenesis. (AU)

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Scientific publications
(References retrieved automatically from Web of Science and SciELO through information on FAPESP grants and their corresponding numbers as mentioned in the publications by the authors)
FANG, QING; BENEDETTI, ANNA FLAVIA FIGUEREDO; MA, QIANYI; GREGORY, LOUISE; LI, JUN Z.; DATTANI, MEHUL; SADEGHI-NEJAD, ABDOLLAH; ARNHOLD, IVO J. P.; MENDONCA, BERENICE BILHARINHO; CAMPER, SALLY A.; et al. HESX1 mutations in patients with congenital hypopituitarism: variable phenotypes with the same genotype. Clinical Endocrinology, v. 85, n. 3, p. 408-414, . (13/00073-8)

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