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. 2014 Dec 16;111(50):17953-8.
doi: 10.1073/pnas.1417438111. Epub 2014 Dec 3.

"V体育安卓版" Functionally compromised CHD7 alleles in patients with isolated GnRH deficiency

Ravikumar Balasubramanian  1 , Jin-Ho Choi  2 , Ludmila Francescatto  3 , Jason Willer  3 , Edward R Horton  4 , Eleni P Asimacopoulos  5 , Konstantina M Stankovic  5 , Lacey Plummer  4 , Cassandra L Buck  4 , Richard Quinton  6 , Todd D Nebesio  7 , Veronica Mericq  8 , Paulina M Merino  8 , Brian F Meyer  9 , Dorota Monies  9 , James F Gusella  10 , Nada Al Tassan  9 , Nicholas Katsanis  3 , William F Crowley Jr  11
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Functionally compromised CHD7 alleles in patients with isolated GnRH deficiency

"VSports app下载" Ravikumar Balasubramanian et al. Proc Natl Acad Sci U S A. .

V体育2025版 - Abstract

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) VSports手机版. 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. .

Keywords: CHARGE syndrome; CHD7; Kallmann syndrome; idiopathic hypogonadotropic hypogondism; missense mutations. V体育安卓版.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
CHD7 protein domains and positions of RSVs identified in CHARGE syndrome and IGD. Both CHARGE- and IGD-associated variants in CHD7 were equally dispersed across its 37 exons without mutational hot spots. Most mutations identified in CHARGE syndrome are nonsense or frameshift, whereas the vast majority of RSVs found in IGD are missense variants. RSVs identified in family members with delayed puberty, anosmia, and unaffected carriers were depicted along with RSVs seen in probands. BRK, Brahma and Kismet domain; CD, chromodomain; DEXHc, DEAD-like helicase superfamily including an ATP-binding domain; NLS, nuclear localization signal.
Fig. 2.
Fig. 2.
Functional assessment of CHD7 RSVs in zebrafish assay. (A) The otic vesicle of control-MO–injected zebrafish contains two otoliths (Inset A). Larva treated with an MO against chd7 show normal (Inset B), three/fused (Inset C), or small (Inset D) or absent (Inset E) otoliths, whereas coinjection of WT human CHD7 rescues the morphant phenotype showing normal two otoliths (Inset F). (B) In vivo rescue assay: Coinjection of human CHD7 mRNA encoding mutant S103T allele along with chd7 MO results in significant rescue of morphant phenotype indistinguishable from WT rescue. Coinjection of chd7 MO with human CHD7 mRNAs encoding the two other control alleles (p.M340V, p.L2984F) from group A (see main text) shows rescue similar to S103T allele. Five IGD-associated CHD7 alleles (p.F1362L, p.G1845R, G1982E, p.I2064V, and p.I2232V) from group B (see main text) were partial LOF alleles (hypomorphs). Of the CHARGE-associated CHD7 alleles (group C, see main text), one was complete LOF (null) (p.I1028V) and two were hypomorphic (p.D1596G and p.D1812H). The remaining CHD7 alleles were benign on the rescue assay. (C) Overexpression of human mutant CHD7 mRNAs in zebrafish: overexpression of the human WT CHD7 mRNA did not induce any appreciable phenotypes. Four IGD-associated CHD7 alleles (p.P940L, p.E1897K, p.T2532M, and p.Q2621E) from group B (see main text) and two CHARGE-associated CHD7 alleles (p. A1289V and p.V1021G) from group C (see main text) showed a dominant effect in the overexpression assay. The remaining CHD7 alleles were benign on the overexpression assay. ***P < 0.0005, **P < 0.005, *P < 0.05; NS, not significant.
Fig. 3.
Fig. 3.
Structural modeling of the CHD7 chromo- and helicase domains (amino acids 799–1511) (A) and SANT domain (amino acids 1964–2115) (B) showing four variants (p.P940L, p.V1021G, p.A1289V, and p.G1982E) that were predicted to be detrimental to protein stability by FoldX algorithm (asterisk).
Fig. 4.
Fig. 4.
Family pedigrees of probands with pathogenic CHD7 mutations. Pedigrees #11, #12, #18, #28, #33, #35, #38, and #44 harbored CHD7 mutations alone, and pedigrees #24 and #25 harbored CHD7 mutations oligogenic with FGFR1 and GNRHR genes, respectively. Among familial cases, pedigree #24 and pedigree #25 display incomplete penetrance for CHD7 mutations and pedigree #18 displays variable expressivity of GnRH deficiency/anosmia phenotypes for the CHD7 mutation. Probands are identified by arrows. “+” indicates WT allele.
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References

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