Mutations in LHX3 result in a new syndrome revealed by combined pituitary hormone deficiency

Netchine, Irène; Sobrier, Marie-Laure; Krude, Heiko; Schnabel, Dirk; Maghnie, M.; Marcos, Élisabeth; Duriez, Bénédicte; Cacheux, Valère; Moers, Arpard V.; Goossens, Michel; Grüters, Annette; Amselem, Serge

doi:10.1038/76041

Cited by 333 publications

(200 citation statements)

References 18 publications

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“…In the cochlea, LHX3 expression is downregulated in postnatal hair cells. Individuals with LHX3 mutations have no gross hearing deficit, indicating that its expression is not essential for some degree of hearing (Gruters et al, 2004;Netchine et al, 2000). The effect of the loss of LHX3 on vestibular function is unknown.…”

Section: Resultsmentioning

confidence: 99%

Expression of LHX3 and SOX2 during mouse inner ear development

Hume

Bratt

Oesterle

2007

Gene Expression Patterns

138

140

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A cascade of transcription factors is believed to regulate the coordinate differentiation of primordial inner ear cells into the subtypes of hair cells and supporting cells. While candidate genes involved in this process have been identified, the temporal and spatial patterns of expression of many of these have not been carefully described during the extended period of inner ear development and functional maturation. We systematically examined the expression of two such transcription factors, LHX3 and SOX2, from the time of hair cell terminal mitoses into adulthood. We show that LHX3 is expressed specifically in auditory and vestibular hair cells soon after terminal mitoses and persists into the adult in vestibular hair cells. While SOX2 expression is widespread in the inner ear sensory epithelia prior to hair cell differentiation, it has a unique pattern of expression in the mature auditory and vestibular organs.

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Section: Resultsmentioning

confidence: 99%

Expression of LHX3 and SOX2 during mouse inner ear development

Hume

Bratt

Oesterle

2007

Gene Expression Patterns

138

140

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“…All characterized patients have combined pituitary hormone deficiency (CPHD) lacking GH, PRL, FSH, LH, and TSH, with normal ACTH levels (Netchine et al, 2000;Bhangoo et al, 2006). This is a similar phenotype to the Lhx3 null mice that lack most hormonesecreting cell types but retain some ACTH-secreting corticotropes.…”

Section: Lhx3mentioning

confidence: 85%

“…The human LHX3 gene maps to chromosome 9 and is composed of seven coding exons and six introns that span ~8.5 kilobases (Netchine et al, 2000;Sloop et al, 2000a;Sloop et al, 2000b). Mammalian LHX3 genes produce two major mRNAs known as LHX3a and LHX3b (Zhadanov et al, 1995b;Sloop et al, 1999;Sloop et al, 2000a).…”

Section: Lhx3mentioning

confidence: 99%

“…Further, as observed for the Lhx3 +/− mouse, heterozygous family members are unaffected. The first classes of LHX3 mutations were described in two unrelated consanguineous families (Netchine et al, 2000). One mutation causes a substitution of a tyrosine residue in the highly conserved LIM2 domain with a cysteine; the other mutation involves a homozygous deletion that results in the loss of the HD.…”

Section: Lhx3mentioning

confidence: 99%

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Roles of the LHX3 and LHX4 LIM-homeodomain factors in pituitary development

Mullen

Colvin

Hunter

et al. 2007

Molecular and Cellular Endocrinology

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The LHX3 and LHX4 LIM-homeodomain transcription factors play essential roles in pituitary gland and nervous system development. Mutations in the genes encoding these regulatory proteins are associated with combined hormone deficiency diseases in humans and animal models. Patients with these diseases have complex syndromes involving short stature, and reproductive and metabolic disorders. Analyses of the features of these diseases and the biochemical properties of the LHX3 and LHX4 proteins will facilitate a better understanding of the molecular pathways that regulate the development of the specialized hormone-secreting cells of the mammalian anterior pituitary gland.

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“…identificaram duas mutações em homozigose no LHX3 (49). A doença tem herança autossômica recessiva e os pacientes apresentam deficiência de GH, gonadotrofinas, TSH e PRL, preservando apenas a função dos corticotrófos.…”

Section: Gene Lhx3unclassified

Genética molecular do eixo hipotálamo-hipófise-gonadal

Costa

Domenice

Corrêa

et al. 2003

Arq Bras Endocrinol Metab

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RESUMONessa revisão, descrevemos os genes que codificam uma rede de fatores de transcrição, proteínas, hormônios, enzimas e receptores expressos nos diversos níveis do eixo hipotálamo-hipófise-gonadal (HHG), e relatamos nossa experiência na identificação e caracterização das mutações identificadas em pacientes com alterações do eixo HHG, incluindo o hipogonadismo hipergonadotrófico e o hipogonadismo hipogonadotrófico isolado ou associado a outras deficiências hormonais hipofisárias, e alterações do desenvolvimento puberal e sexual. Até o momento, foram identificados 15 genes que atuam no desenvolvimento e função do eixo HHG: KAL, SF1, DAX1, LEPTINA, PC1, GnRH, GnRHR, HESX1, LHX3, PROP1, FSHR, LHR, FSHβ, LHβ e FGFR1. A maioria das mutações identificadas em nossa casuística foi descrita pela primeira vez na literatura e freqüentemente esteve associada a novos aspectos clínicos e hormonais das doenças. As conseqüências dessas mutações, caracterizadas por estudos in vitro, contribuíram para um melhor entendimento da estrutura e função das proteínas codificadas por esses genes. A união do diagnóstico clínico, hormonal e molecular dos distúr-bios do eixo HHG contribui significantemente para aprimorar o conhecimento e, conseqüentemente, o diagnóstico e a terapêutica destes pacientes. In this review, we described the genes that encode an array of transcription factors, matrix proteins, hormones, enzymes and receptors that are expressed at multiple levels of the hypothalamic-pituitary-gonadal axis (HPG). In addition, we reported our experience in the identification and characterization of naturally occurring mutations in patients affected by HPG disorders, including hypergonadotropic hypogonadism and hypogonadotropic hypogonadism, isolated or associated with others pituitary hormonal deficiencies, and abnormalities of pubertal and sexual development. To date, fifteen distinct genes implicated with HPG axis development and function were identified: KAL, SF1, DAX1, LEPTIN, PC1, GnRH, GnRHR, HESX1, LHX3, PROP1, FSHR, LHR, LHβ, FSHβ and FGFR1. Most mutations identified in our cohort were described for the first time in literature and they frequently were associated with new clinical and hormonal aspects of the diseases. Characterization of the consequences of these mutations in in vitro studies have provided increased understanding of the structure and function of the proteins encoded by these genes. The combined clinical, hormonal and molecular diagnosis of HPG disorders have helped significantly to improve the knowledge and, consequently, the diagnosis and treatment of these patients.

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Mutations in LHX3 result in a new syndrome revealed by combined pituitary hormone deficiency

Cited by 333 publications

References 18 publications

Expression of LHX3 and SOX2 during mouse inner ear development

Expression of LHX3 and SOX2 during mouse inner ear development

Roles of the LHX3 and LHX4 LIM-homeodomain factors in pituitary development

Genética molecular do eixo hipotálamo-hipófise-gonadal

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