Mutations in CHD7, Encoding a Chromatin-Remodeling Protein, Cause Idiopathic Hypogonadotropic Hypogonadism and Kallmann Syndrome
| Autor: | Ingo Kurth, Gil Bu Kang, Metin Ozata, Irene Meliciani, Mustafa Tekin, Richard J. Sherins, Yang Shi, Wolfgang Wenzel, Georg Rosenberger, Fei Lan, Soo Hyun Eom, Lawrence C. Layman, James F. Gusella, David P. Bick, Hyung Goo Kim, Steven L. Walker |
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| Rok vydání: | 2008 |
| Předmět: |
Male
medicine.medical_specialty Kallmann syndrome Molecular Sequence Data Molecular Conformation 030209 endocrinology & metabolism Biology medicine.disease_cause Human puberty 03 medical and health sciences CHARGE syndrome 0302 clinical medicine Hypogonadotropic hypogonadism Report Internal medicine Genetics medicine Humans Missense mutation Genetics(clinical) Amino Acid Sequence Genetics (clinical) 030304 developmental biology 0303 health sciences Mutation Base Sequence Sequence Homology Amino Acid Genetic heterogeneity Hypogonadism DNA Helicases Exons Kallmann Syndrome medicine.disease Chromatin Protein Structure Tertiary 3. Good health DNA-Binding Proteins body regions Endocrinology Female Congenital Hypogonadotropic Hypogonadism |
| Zdroj: | The American Journal of Human Genetics. 83:511-519 |
| ISSN: | 0002-9297 |
| DOI: | 10.1016/j.ajhg.2008.09.005 |
| Popis: | 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 inor = 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. |
| Databáze: | OpenAIRE |
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