title: Mutation analyses in pedigrees and sporadic cases of ethnic Han Chinese Kallmann syndrome patients.
abstract: Kallmann syndrome, a form of idiopathic hypogonadotropic hypogonadism, is characterized by developmental abnormalities of the reproductive system and abnormal olfaction. Despite association of certain genes with idiopathic hypogonadotropic hypogonadism, the genetic inheritance and expression are complex and incompletely known. In the present study, seven Kallmann syndrome pedigrees in an ethnic Han Chinese population were screened for genetic mutations. The exons and intron-exon boundaries of 19 idiopathic hypogonadotropic hypogonadism (idiopathic hypogonadotropic hypogonadism)-related genes in seven Chinese Kallmann syndrome pedigrees were sequenced. Detected mutations were also tested in 70 sporadic Kallmann syndrome cases and 200 Chinese healthy controls. In pedigrees 1, 2, and 7, the secondary sex characteristics were poorly developed and the patients' sense of smell was severely or completely lost. We detected a genetic mutation in five of the seven pedigrees: homozygous KAL1 p.R191ter (pedigree 1); homozygous KAL1 p.C13ter (pedigree 2; a novel mutation); heterozygous FGFR1 p.R250W (pedigree 3); and homozygous PROKR2 p.Y113H (pedigrees 4 and 5). No genetic change of the assayed genes was detected in pedigrees 6 and 7. Among the 70 sporadic cases, we detected one homozygous and one heterozygous PROKR2 p.Y113H mutation. This mutation was also detected heterozygously in 2/200 normal controls and its pathogenicity is likely questionable. The genetics and genotype-phenotype relationships in Kallmann syndrome are complicated. Classical monogenic inheritance does not explain the full range of genetic inheritance of Kallmann syndrome patients. Because of stochastic nature of genetic mutations, exome analyses of Kallmann syndrome patients may provide novel insights.
authors.affiliation: Department of Endocrinology, Chinese PLA General Hospital, Beijing 100853, China.
authors.forename: Wei-Jun
authors.initials: WJ
authors.lastname: Gu
authors.affiliation: Department of Endocrinology, Chinese PLA General Hospital, Beijing 100853, China.
authors.forename: Qian
authors.initials: Q
authors.lastname: Zhang
authors.affiliation: Department of Endocrinology, Chinese PLA General Hospital, Beijing 100853, China.
authors.forename: Ying-Qian
authors.initials: YQ
authors.lastname: Wang
authors.affiliation: Department of Endocrinology, Chinese PLA General Hospital, Beijing 100853, China.
authors.forename: Guo-Qing
authors.initials: GQ
authors.lastname: Yang
authors.affiliation: Department of Endocrinology, Peking University the Third Hospital, Beijing 100191, China.
authors.forename: Tian-Pei
authors.initials: TP
authors.lastname: Hong
authors.affiliation: Department of Endocrinology, Drum Tower Hospital, Affiliated to Medical College of Nanjing University, Nanjing 210008, China.
authors.forename: Da-Long
authors.initials: DL
authors.lastname: Zhu
authors.affiliation: Department of Endocrinology, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China.
authors.forename: Jin-Kui
authors.initials: JK
authors.lastname: Yang
authors.affiliation: Department of Endocrinology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China.
authors.forename: Guang
authors.initials: G
authors.lastname: Ning
authors.affiliation: Department of Endocrinology, Chinese PLA General Hospital, Beijing 100853, China.
authors.forename: Nan
authors.initials: N
authors.lastname: Jin
authors.affiliation: Department of Endocrinology, Chinese PLA General Hospital, Beijing 100853, China.
authors.forename: Kang
authors.initials: K
authors.lastname: Chen
authors.affiliation: Department of Endocrinology, Chinese PLA General Hospital, Beijing 100853, China.
authors.forename: Li
authors.initials: L
authors.lastname: Zang
authors.affiliation: Department of Endocrinology, Chinese PLA General Hospital, Beijing 100853, China.
authors.forename: An-Ping
authors.initials: AP
authors.lastname: Wang
authors.affiliation: Department of Endocrinology, Chinese PLA General Hospital, Beijing 100853, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Du
authors.affiliation: Department of Endocrinology, Chinese PLA General Hospital, Beijing 100853, China.
authors.forename: Xian-Ling
authors.initials: XL
authors.lastname: Wang
authors.affiliation: Department of Endocrinology, Chinese PLA General Hospital, Beijing 100853, China.
authors.forename: Li-Juan
authors.initials: LJ
authors.lastname: Yang
authors.affiliation: Department of Endocrinology, Chinese PLA General Hospital, Beijing 100853, China.
authors.forename: Jian-Ming
authors.initials: JM
authors.lastname: Ba
authors.affiliation: Department of Endocrinology, Chinese PLA General Hospital, Beijing 100853, China.
authors.forename: Zhao-Hui
authors.initials: ZH
authors.lastname: Lv
authors.affiliation: Department of Endocrinology, Chinese PLA General Hospital, Beijing 100853, China.
authors.forename: Jing-Tao
authors.initials: JT
authors.lastname: Dou
authors.affiliation: Department of Endocrinology, Chinese PLA General Hospital, Beijing 100853, China muyiming@301hospital.com.cn.
authors.forename: Yi-Ming
authors.initials: YM
authors.lastname: Mu
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D002648:Child; D002681:China; D018389:Codon, Nonsense; D004252:DNA Mutational Analysis; D005091:Exons; D016326:Extracellular Matrix Proteins / Q000235:genetics; D005192:Family Health; D005260:Female; D056726:Genetic Association Studies; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007006:Hypogonadism / Q000208:ethnology / Q000235:genetics; D007438:Introns; D017436:Kallmann Syndrome / Q000208:ethnology* / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009419:Nerve Tissue Proteins / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000235:genetics; D018000:Receptors, Peptide / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D055815:Young Adult
chemical_list: C076266:ANOS1 protein, human; D018389:Codon, Nonsense; D016326:Extracellular Matrix Proteins; D009419:Nerve Tissue Proteins; C470838:PROKR2 protein, human; D043562:Receptors, G-Protein-Coupled; D018000:Receptors, Peptide; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1
keywords: FGFR1; KAL1; Kallmann syndrome; PROKR2; complex disease; idiopathic hypogonadotropic hypogonadism; polygenic inheritance