Study of smell and reproductive organs in a mouse model for CHARGE syndrome

Bergman, Jorieke E. H.; Bosman, Erika A.; Ravenswaaij-Arts, Conny M. A. van; Steel, Karen P.

doi:10.1038/ejhg.2009.158

Cited by 49 publications

(51 citation statements)

References 34 publications

(48 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Thus, we mated Plxnd1 +/-females with Chd7 +/-males (41) and examined the innervation of the ME in single and compound heterozygous mice. We found that fewer GnRH-positive neuron fibers projected to the ME in the hypothalamus of their Chd7 +/-male offspring compared with that seen in their WT littermates ( Figure 10E, top panels), consistent with previous observations (42). Importantly, the finding that jci.org Volume 125 Number 6 June 2015…”

Section: Sema3esupporting

confidence: 81%

Dysfunctional SEMA3E signaling underlies gonadotropin-releasing hormone neuron deficiency in Kallmann syndrome

Cariboni¹,

Andrè²,

Chauvet³

et al. 2015

J. Clin. Invest.

102

View full text Add to dashboard Cite

International audienceIndividuals with an inherited deficiency in gonadotropin-releasing hormone (GnRH) have impaired sexual reproduction. Previous genetic linkage studies and sequencing of plausible gene candidates have identified mutations associated with inherited GnRH deficiency, but the small number of affected families and limited success in validating candidates have impeded genetic diagnoses for most patients. Using a combination of exome sequencing and computational modeling, we have identified a shared point mutation in semaphorin 3E (SEMA3E) in 2 brothers with Kallmann syndrome (KS), which causes inherited GnRH deficiency. Recombinant wild-type SEMA3E protected maturing GnRH neurons from cell death by triggering a plexin D1-dependent (PLXND1-dependent) activation of PI3K-mediated survival signaling. In contrast, recombinant SEMA3E carrying the KS-associated mutation did not protect GnRH neurons from death. In murine models, lack of either SEMA3E or PLXND1 increased apoptosis of GnRH neurons in the developing brain, reducing innervation of the adult median eminence by GnRH-positive neurites. GnRH neuron deficiency in male mice was accompanied by impaired testes growth, a characteristic feature of KS. Together, these results identify SEMA3E as an essential gene for GnRH neuron development, uncover a neurotrophic function for SEMA3E in the developing brain, and elucidate SEMA3E/PLXND1/PI3K signaling as a mechanism that prevents GnRH neuron deficiency

show abstract

Section: Sema3esupporting

confidence: 81%

Dysfunctional SEMA3E signaling underlies gonadotropin-releasing hormone neuron deficiency in Kallmann syndrome

Cariboni¹,

Andrè²,

Chauvet³

et al. 2015

J. Clin. Invest.

102

View full text Add to dashboard Cite

show abstract

“…Mice with complete Chd7 deficiency mirror the observed human phenotypes (delayed puberty, genital hypoplasia, hypogonadotropism) and display neurodevelopmental defects, including reduced GnRH neurons in the hypothalamus and reduced expression of FGFR1 in the olfactory placode (30,31). Recent work also suggests that CHD7 regulates genes involved in neural crest guidance (32), and there is increasing evidence that KS may also result from impaired neural crest guidance (33).…”

Section: Discussionmentioning

confidence: 99%

Functionally compromised CHD7 alleles in patients with isolated GnRH deficiency

Balasubramanian¹,

Choi

Francescatto

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Inactivating mutations in chromodomain helicase DNA binding protein 7 (CHD7) cause CHARGE syndrome, a severe multiorgan system disorder of which Isolated gonadotropin-releasing hormone (GnRH) deficiency (IGD) is a minor feature. Recent reports have described predominantly missense CHD7 alleles in IGD patients, but it is unclear if these alleles are relevant to causality or overall genetic burden of Kallmann syndrome (KS) and normosmic form of IGD. To address this question, we sequenced CHD7 in 783 well-phenotyped IGD patients lacking full CHARGE features; we identified nonsynonymous rare sequence variants in 5.2% of the IGD cohort (73% missense and 27% splice variants). Functional analyses in zebrafish using a surrogate otolith assay of a representative set of these CHD7 alleles showed that rare sequence variants observed in controls showed no altered function. In contrast, 75% of the IGD-associated alleles were deleterious and resulted in both KS and normosmic IGD. In two families, pathogenic mutations in CHD7 coexisted with mutations in other known IGD genes. Taken together, our data suggest that rare deleterious CHD7 alleles contribute to the mutational burden of patients with both KS and normosmic forms of IGD in the absence of full CHARGE syndrome. These findings (i) implicate a unique role or preferential sensitivity for CHD7 in the ontogeny of GnRH neurons, (ii) reiterate the emerging genetic complexity of this family of IGD disorders, and (iii) demonstrate how the coordinated use of well-phenotyped cohorts, families, and functional studies can inform genetic architecture and provide insights into the developmental biology of cellular systems.CHD7 | Kallmann syndrome | idiopathic hypogonadotropic hypogondism | CHARGE syndrome | missense mutations

show abstract

“…Mice with heterozygous Chd7 mutations show semicircular canal defects, septal heart defects, cleft palate, choanal atresia, hyposmia, olfactory bulb anomalies, testes hypoplasia, hearing loss, and low body weight [Bosman et al, 2005;Adams et al, 2007;Hurd et al, 2007, Layman et al, 2009;Bergman et al, 2010 ]. Other CHARGE features, e.g.…”

Section: Discussionmentioning

confidence: 99%

More Clinical Overlap between 22q11.2 Deletion Syndrome and CHARGE Syndrome than Often Anticipated

et al. 2013

View full text Add to dashboard Cite

CHARGE (coloboma, heart defects, atresia of choanae, retardation of growth and development, genital hypoplasia, and ear abnormalities) and 22q11.2 deletion syndromes are variable, congenital malformation syndromes that show considerable phenotypic overlap. We further explored this clinical overlap and proposed recommendations for the genetic diagnosis of both syndromes. We described 2 patients clinically diagnosed with CHARGE syndrome, who were found to carry a 22q11.2 deletion, and searched the literature for more cases. In addition, we screened our cohort of CHD7 mutation carriers (n = 802) for typical 22q11.2 deletion features and studied CHD7 in 20 patients with phenotypically 22q11.2 deletion syndrome but without haploinsufficiency of TBX1. In total, we identified 5 patients with a clinical diagnosis of CHARGE syndrome and a proven 22q11.2 deletion. Typical 22q11.2 deletion features were found in 30 patients (30/802, 3.7%) of our CHD7 mutation-positive cohort. We found truncating CHD7 mutations in 5/20 patients with phenotypically 22q11.2 deletion syndrome. Differentiating between CHARGE and 22q11.2 deletion syndromes can be challenging. CHD7 and TBX1 probably share a molecular pathway or have common target genes in affected organs. We strongly recommend performing CHD7 analysis in patients with a 22q11.2 deletion phenotype without TBX1 haploinsufficiency and conversely, performing a genome-wide array in CHARGE syndrome patients without a CHD7 mutation.

show abstract

Study of smell and reproductive organs in a mouse model for CHARGE syndrome

Cited by 49 publications

References 34 publications

Dysfunctional SEMA3E signaling underlies gonadotropin-releasing hormone neuron deficiency in Kallmann syndrome

Dysfunctional SEMA3E signaling underlies gonadotropin-releasing hormone neuron deficiency in Kallmann syndrome

Functionally compromised CHD7 alleles in patients with isolated GnRH deficiency

More Clinical Overlap between 22q11.2 Deletion Syndrome and CHARGE Syndrome than Often Anticipated

Contact Info

Product

Resources

About