SEMA3A deletion in a family with Kallmann syndrome validates the role of semaphorin 3A in human puberty and olfactory system development

Young, Jacques; Métay, Corinne; Bouligand, Jérôme; Tou, Bassim; Francou, Bruno; Maione, Luigi; Tosca, Lucie; Sarfati, Julie; Brioude, Frédéric; Esteva, Blandine; Briand-Suleau, Audrey; Brisset, Sophie; Goossens, Michel; Tachdjian, Gérard; Guiochon‐Mantel, Anne

doi:10.1093/humrep/des022

Cited by 126 publications

(94 citation statements)

References 34 publications

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“…The authors propose that monoallelic mutations in SEMA3A are insufficient to induce olfactory bulb agenesis, but probably act in concert with other mutations in genes regulating the semaphorin-3A signaling pathway. A similar conclusion was drawn by Young et al [3] who also reported a SEMA-3A mutation in a family with KS.…”

Section: Sema-3a Is a New Mutated Gene In Kallmann Syndrome (Ks) Witsupporting

confidence: 87%

Neuroendocrinology

Chevrier¹,

Tata²,

Roux³

2013

Yearbook of Pediatric Endocrinology 2013

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New mechanisms Circadian rhythm and metabolismTwo different mechanisms by which circadian clock and metabolism are linked are presented in the two following papers. Regulation of circadian behavior and metabolism by synthetic REV-ERB agonistsSolt LA, Wang Y, Banerjee S, Hughes T, Kojetin DJ, Lundasen T, Shin Y, Liu J, Cameron MD, Noel R, Yoo SH, Takahashi JS, Butler AA, Kamenecka TM, Burris TP Department of Molecular Therapeutics, The Scripps Research Institute, Jupiter, FL, USA Nature 2012;485:62-68 Background: The nuclear receptors REV-ERB-␣ and REV-ERB-␤ have an important role in regulation of core clock genes expression driving circadian activity and metabolism. Agonists of these receptors could be of interest to regulate circadian rhythm disorders and metabolic disorders. Methods: The authors synthesized agonists of REV-ERB-␣ and REV-ERB-␤ and tested their effects in circadian activity and metabolic regulation. Results: SR9011 and SR9009 are two synthetic agonists of REV-ERB-␣ and REV-ERB-␤. In vivo, these compounds altered circadian behaviors and the expression of core clock genes in the hypothalamus of mice. The expression of metabolic genes in liver, skeletal muscle and adipose tissue was also altered, which resulted in increased energy expenditure. In obese mice, these agonists decreased body weight. Conclusion: Agonists of REV-ERB-␣ and REV-ERB-␤ appeared to be useful pharmacological tools for the treatment of sleep disorders and metabolic diseases.REV-ERB-␣ and REV-ERB-␤ are nuclear receptors regulating core clock genes. These receptors also play a key role in lipid synthesis. This study proposed a molecular mechanism linking circadian clock and metabolism. In fact, the authors described two new synthetic agonists of REV-ERB-␣ and REV-ERB-␤ that disrupted circadian activity and repressed clock gene expression in the hypothalamus. Interestingly, the expression of clock genes in peripheral tissues was not affected by these treatments. The circadian alteration induced by agonists of REV-ERB-␣ and REV-ERB-␤ was accompanied by changes in expression of genes involved in metabolism leading to a loss of body weight and to an increase of energy expenditure. These metabolic variations were also seen in obese mice. This study brings new insight about the development of compounds targeting REV-ERB-␣ and REV-ERB-␤ and more widely the circadian clock to treat metabolic disorders such as obesity. Circadian rhythm of redox state regulates excitability in suprachiasmatic nucleus neuronsWang TA, Yu YV, Govindaiah G, Ye X, Artinian L, Coleman TP, Sweedler JV, Cox CL, Gillette MU Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL, USA Science 2012;337:839-842 Background: Circadian rhythms are orchestrated in the suprachiasmatic nucleus (SCN) by a central circadian clock and are controlled by the circadian expression of clock genes. Redox state can regulate the expression of these genes. However, nothing was known about a potential non-transcriptional regulat...

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Section: Sema-3a Is a New Mutated Gene In Kallmann Syndrome (Ks) Witsupporting

confidence: 87%

Neuroendocrinology

Chevrier¹,

Tata²,

Roux³

2013

Yearbook of Pediatric Endocrinology 2013

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“…Mutations in genes such as GNRH1, GRNHR, KISS1 or KISS1R (7, 8,9,10,11,12,13,14) can impair the action (or secretion) of GnRH, resulting in normosmic CHH. In contrast, mutations in genes impacting the migration of GnRH neurons from the olfactory placode during development (ANOS1, SEMA3A, IL17RD, SOX10 and FEZF1) (15,16,17,18,19,20,21) result in KS. KAL1, recently renamed ANOS1, was the first X-linked gene implicated in CHH (15,16,22,23).…”

Section: Pathophysiology and Genetics Of Chhmentioning

confidence: 98%

MANAGEMENT OF ENDOCRINE DISEASE: Reversible hypogonadotropic hypogonadism

Dwyer

Raivio

Pitteloud

2016

European Journal of Endocrinology

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Congenital hypogonadotropic hypogonadism (CHH) is characterized by lack of puberty and infertility. Traditionally, it has been considered a life-long condition yet cases of reversibility have been described wherein patients spontaneously recover function of the reproductive axis following treatment. Reversibility occurs in both male and female CHH cases and appears to be more common (~10-15%) than previously thought. These reversal patients span a range of GnRH deficiency from mild to severe and many reversal patients harbor mutations in genes underlying CHH. However, to date there are no clear factors for predicting reversible CHH. Importantly, recovery of reproductive axis function may not be permanent. Thus, CHH is not always life-long and the incidence of reversal warrants periodic treatment withdrawal with close monitoring and follow-up. Reversible CHH highlights the importance of environmental (epigenetic) factors such as sex steroid treatment on the reproductive axis in modifying the phenotype. This review provides an overview and an update on what is known about this phenomenon.

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“…Genes encoding fibroblast growth factor 8 (FGF8) signalling pathway proteins, [17][18][19][20][21][22] chromodomain helicase DNA-binding protein 7 (CHD7) [23][24][25][26][27] and sex determining region Y-Box 10 (SOX10) 28,29 affect the neurogenic niche in the nasal area and craniofacial development. Conversely, Kallmann syndrome protein, which is now officially known as anosmin 1 (encoded by KAL1; following nomenclature change, the gene is now denoted as ANOS1), 2 prokineticin-2 and prokineticin receptor 2 (encoded by PROK2 and PROKR2, respectively), [30][31][32][33] WD repeat domain 11 (encoded by WDR11), 34,35 semaphorin 3A (encoded by SEMA3A) [36][37][38] and FEZ family zinc finger 1 (encoded by FEZF1) 39 influence migration of GnRH neurons.…”

Section: Biology Of the Gnrh Neuronal Systemmentioning

confidence: 99%

“…117,118 To date, >25 different genes have been implicated in Kallmann syndrome and/or CHH, which accounts for ~50% of cases. 21 Causative genes for Kallmann syndrome include: KAL1 (ANOS1) in the X-linked form; FGFR1 (encoding fibroblast growth factor receptor 1), 17,18 FGF8, 19,119 CHD7, [23][24][25][26][27] HS6ST1 (encoding heparan-sulphate 6-O-sulphotransferase 1), 20 SOX10, 28,29 SEMA3A (encoding semaphorin-3A), [36][37][38] WDR11 (encoding WD repeat-containing protein 11) 34,35 and IL17RD (encoding interleukin-17 receptor D) 21 in the autosomal dominant form; and PROKR2 and/or PROK2, [30][31][32][33] and FEZF1 39 in the autosomal recessive form, even though it should be noted that most patients carrying mutations in PROKR2 or PROK2 carry these mutations in the heterozygous state. 120,121 Genes involved in CHH that are associated with a normal sense of smell include GNRHR (encoding gonadotropinreleasing hormone receptor), 122,123 GNRH1 (encoding gonadotropin-releasing hormone 1), 124,125 KISS1R, 41,42 KISS1, 40,126 TACR3 and TAC3.…”

Section: Genetics Of Chhmentioning

confidence: 99%

European Consensus Statement on congenital hypogonadotropic hypogonadism—pathogenesis, diagnosis and treatment

et al. 2015

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| Congenital hypogonadotropic hypogonadism (CHH) is a rare disorder caused by the deficient production, secretion or action of gonadotropin-releasing hormone (GnRH), which is the master hormone regulating the reproductive axis. CHH is clinically and genetically heterogeneous, with >25 different causal genes identified to date. Clinically, the disorder is characterized by an absence of puberty and infertility. The association of CHH with a defective sense of smell (anosmia or hyposmia), which is found in ~50% of patients with CHH is termed Kallmann syndrome and results from incomplete embryonic migration of GnRHsynthesizing neurons. CHH can be challenging to diagnose, particularly when attempting to differentiate it from constitutional delay of puberty. A timely diagnosis and treatment to induce puberty can be beneficial for sexual, bone and metabolic health, and might help minimize some of the psychological effects of CHH. In most cases, fertility can be induced using specialized treatment regimens and several predictors of outcome have been identified. Patients typically require lifelong treatment, yet ~10-20% of patients exhibit a spontaneous recovery of reproductive function. This Consensus Statement summarizes approaches for the diagnosis and treatment of CHH and discusses important unanswered questions in the field.

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SEMA3A deletion in a family with Kallmann syndrome validates the role of semaphorin 3A in human puberty and olfactory system development

Abstract: SEMA3A is therefore a new gene whose loss-of-function is involved in KS. These findings validate the specific role of semaphorin 3A in the development of the olfactory system and in neuronal control of puberty in humans.

Cited by 126 publications

References 34 publications

Neuroendocrinology

Neuroendocrinology

MANAGEMENT OF ENDOCRINE DISEASE: Reversible hypogonadotropic hypogonadism

European Consensus Statement on congenital hypogonadotropic hypogonadism—pathogenesis, diagnosis and treatment

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