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Mutations in CHD7, Encoding a Chromatin-Remodeling Protein, Cause Idiopathic Hypogonadotropic Hypogonadism and Kallmann Syndrome
被引:232
作者:
Kim, Hyung-Goo
[4
,5
]
Kurth, Ingo
[6
]
Lan, Fei
[7
]
Meliciani, Irene
[8
]
Wenzel, Wolfgang
[9
]
Eom, Soo Hyun
[10
]
Kang, Gil Bu
[10
]
Rosenberger, Georg
[6
]
Tekin, Mustafa
[11
]
Ozata, Metin
[12
]
Bick, David P.
[13
,14
]
Sherins, Richard J.
[15
]
Walker, Steven L.
[1
,2
,3
,16
]
Shi, Yang
[7
]
Gusella, James F.
[4
,5
]
Layman, Lawrence C.
[1
,2
,3
,16
]
机构:
[1] Med Coll Georgia, Dept Obstet & Gynecol, Sect Reprod Endocrinol Infertil & Genet, Augusta, GA 30912 USA
[2] Med Coll Georgia, Inst Mol Med & Genet, Reprod Med Program, Augusta, GA 30912 USA
[3] Med Coll Georgia, Inst Mol Med & Genet, Dev Neuobiol Program, Augusta, GA 30912 USA
[4] Massachusetts Gen Hosp, Ctr Human Genet Res, Mol Neurogenet Unit, Boston, MA 02114 USA
[5] Harvard Univ, Sch Med, Dept Genet, Boston, MA 02114 USA
[6] Univ Klinikum Hamburg Eppendorf, Inst Human Genet, D-20246 Hamburg, Germany
[7] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA
[8] Univ Roma La Sapienza, Fac Sci, I-00185 Rome, Italy
[9] Forschungszentrum Karlsruhe, Inst Nanotechnol, D-76021 Karlsruhe, Germany
[10] Gwangju Inst Sci & Technol, Cell Dynam Res Ctr, Dept Life Sci, Kwangju 500712, South Korea
[11] Ankara Univ, Sch Med, Dept Pediat, Div Clin Mol Pathol & Genet, TR-06100 Ankara, Turkey
[12] GATA Haydarpasa Training Hosp, Dept Endocrinol, TR-34660 Istanbul, Turkey
[13] Med Coll Wisconsin, Dept Pediat, Div Med Genet, Milwaukee, WI 53226 USA
[14] Med Coll Wisconsin, Dept Obstet & Gynecol, Milwaukee, WI 53226 USA
[15] Columbia Fertil Associates, Washington, DC 20037 USA
[16] Med Coll Georgia, Neurosci Program, Augusta, GA 30912 USA
基金:
美国国家卫生研究院;
关键词:
D O I:
10.1016/j.ajhg.2008.09.005
中图分类号:
Q3 [遗传学];
学科分类号:
071007 ;
090102 ;
摘要:
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 >= 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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页码:511 / 519
页数:9
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