Mutations in CHD7, Encoding a Chromatin-Remodeling Protein, Cause Idiopathic Hypogonadotropic Hypogonadism and Kallmann Syndrome
Open accessAbstract
CHARGE syndrome and Kallmann syndrome (KS) are two distinct developmental disorders sharing overlapping features of impaired olfaction and hypogonadism. KS is a genetically heterogeneous disorder consisting of idiopathic hypogonadotropic hypogonadism (IHH) and anosmia, and is most commonly due to KAL1 or FGFR1 mutations. CHARGE syndrome, a multisystem autosomal-dominant disorder, is caused by CHD7 mutations. We hypothesized that CHD7 would be involved in the pathogenesis of IHH and KS (IHH/KS) without the CHARGE phenotype and that IHH/KS represents a milder allelic variant of CHARGE syndrome. Mutation screening of the 37 protein-coding exons of CHD7 was performed in 101 IHH/KS patients without a CHARGE phenotype. In an additional 96 IHH/KS patients, exons 6-10, encoding the conserved chromodomains, were sequenced. RT-PCR, SIFT, protein-structure analysis, and in situ hybridization were performed for additional supportive evidence. Seven heterozygous mutations, two splice and five missense, which were absent in > or = 180 controls, were identified in three sporadic KS and four sporadic normosmic IHH patients. Three mutations affect chromodomains critical for proper CHD7 function in chromatin remodeling and transcriptional regulation, whereas the other four affect conserved residues, suggesting that they are deleterious. CHD7's role is further corroborated by specific expression in IHH/KS-relevant tissues and appropriate developmental expression. Sporadic CHD7 mutations occur in 6% of IHH/KS patients. CHD7 represents the first identified chromatin-remodeling protein with a role in human puberty and the second gene to cause both normosmic IHH and KS in humans. Our findings indicate that both normosmic IHH and KS are mild allelic variants of CHARGE syndrome and are caused by CHD7 mutations.
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These CHD7 mutations are believed to result in a milder form of CHARGE syndrome that manifests as normosmic IHH or Kallmann syndrome.
“These mutations are believed to result in a milder form of CHARGE syndrome that manifests as normosmic IHH or Kallmann syndrome.”
From The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism (2009) · cites this paper as [33]
Seven mutations in CHD7 were identified in patients with sporadic normosmic IHH or Kallmann syndrome who were not diagnosed with CHARGE syndrome.
“Furthermore, seven mutations in CHD7 were recently identified in patients with sporadic, normosmic IHH or Kallmann syndrome who were not diagnosed as having CHARGE syndrome.”
From The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism (2009) · cites this paper as [33]
Mutations in CHD7 are predicted to account for 6% of all IHH cases.
“Mutations in CHD7 are predicted to account for 6% of all IHH cases (Table 1).”
From The genetic and molecular basis of idiopathic hypogonadotropic hypogonadism (2009) · cites this paper as [33]
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- Authors
- Kim, H.-G., Kurth, I., Lan, F., Meliciani, I., Wenzel, W., Eom, S. H., Kang, G. B., Rosenberger, G., Tekin, M., Ozata, M., Bick, D. P., Sherins, R. J., Walker, S. L., Shi, Y., Gusella, J. F., & Layman, L. C.
- Affiliations
- Harvard University (US)
- University Medical Center Hamburg-Eppendorf (DE)
- Sapienza University of Rome (IT)
- Karlsruhe Institute of Technology (DE)
- Gwangju Institute of Science and Technology (KR)
- Ankara University (TR)
- Medical College of Wisconsin (US)
- Augusta University (US)
- Corresponding author
- Layman, Lawrence C.
- ORCID
- Venue
- The American Journal of Human Genetics
- Publisher
- Elsevier BV
- Published
- 2008-10
- Volume
- 83
- Issue
- 4
- Pages
- 511-519
- ISSN
- 0002-9297 (ISSN-L)
- PMC
- PMC2561938
- OpenAlex
- W2079455457
- Cited by
- 338
- References
- 45
- Citations by year
- 2026: 6 · 2025: 8 · 2024: 10 · 2023: 16 · 2022: 16 · 2021: 22 · 2020: 20 · 2019: 14 · 2018: 15 · 2017: 19 · 2016: 15 · 2015: 20 · 2014: 26 · 2013: 26 · 2012: 25
- FWCI
- 12.15
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The American Journal of Human Genetics (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Institute of General Medical Sciences (GM061354, P01GM061354)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R29HD033004, R01HD033004, HD040287, K24HD040287, HD 33004)
- Topics
- Health Sciences › Medicine › Genetics › Congenital Ear and Nasal Anomalies
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Clinical Aspects of Sex Determination and Chromosomal Abnormalities
- Keywords
- CHD7, idiopathic hypogonadotropic hypogonadism, Kallmann syndrome, CHARGE syndrome, chromatin remodeling, chromodomain, missense mutations, splicing mutation, anosmia, olfaction, puberty, allelic variants, KAL1, FGFR1
- MeSH terms
- Amino Acid Sequence, Base Sequence, Chromatin, DNA Helicases, DNA-Binding Proteins, Exons, Female, Humans, Hypogonadism, Male, Molecular Conformation, Molecular Sequence Data, Mutation, Sequence Homology, Amino Acid, Protein Structure, Tertiary, Kallmann Syndrome
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