不同基因突变对特发性低促性腺激素性性腺功能减退症患者的临床特点、隐睾和生精疗效的影响
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摘要
[目的]
(1)在中国男性特发性低促性腺激素性性腺功能减退症(IHH)患者中,明确基因突变的发生率是多少?各致病基因比重如何?
(2)不同基因所致IHH,各有何临床特点?这些临床特点,能否提示某种基因突变?
(3)有多少患者存在双(寡)基因突变?和单基因突变的患者相比,双(寡)基因突变的IHH患者,是否存在更严重的性腺轴功能损伤?
(4)根据基因检测和临床表现(有无嗅觉)对IHH患者进行亚组分析,评价不同患者人群的精子生成差异。
[方法]
(1)基因研究：采用基因芯片(NimbleGen2.1M基因芯片组),对IHH患者和部分家属的19个IHH基因外显子和相邻内含子进行检测。对每一个改变的碱基,通过多个数据库进行多态性分析或突变状态的检测。利用SIFT和Polyphen-2计算机模拟软件,对突变基因及其编码蛋白质的功能进行预测。对明确的基因突变检测结果,用经典sanger PCR方法进行验证。根据基因突变情况,把患者分为明确基因突变组、可疑基因突变组、无效基因突变组和未检测到基因突变组。
(2)临床研究：收集患者的临床资料,包括性别、年龄、初诊和随访中的睾丸体积、垂体前叶激素水平、生精治疗后的睾酮水平、睾丸体积、精子数量和爱人妊娠情况。根据睾丸体积和生精治疗的效果,对患者的精子生成能力进行半定量评分,分为0、1、2、3四个等级,称为“生精指数”。分数越高,提示生精治疗的效果越好,产生精子的可能性越大,精子数量越多。
(3)统计学方法：不同组之间的比较：对符合正态分布的连续性变量,采用非配对t检验；对符合正态分布的有序分类变量,采用Kruskal-Wallis检验。除非特殊说明,数据以平均值±标准误(Mean±SE)表示。
[结果]
(1)男性259例IHH患者中,明确基因突变87例(33.6%),可疑基因突变35例(13.5%),无效基因突变69例(26.8%),未检测到已知基因突变68例(26.2%)。明确基因突变是指,基因突变已被报道过,或已通过体外试验验证了功能缺陷,或发生于剪切位点的碱基改变,或通过计算机模拟软件(SIFT和Polyphen-2检测方法)提示蛋白质功能受到明显损害。可疑基因突变是指：发生率小于1%的SNP,或以常染色体隐性遗传方式的致病基因发生杂合突变(即两个等位基因中,有一个发生可导致氨基酸变化的突变)。无效基因突变是指,内含子(非剪切位点)存在异常或外显子发生同义突变。未检测到基因突变是指,IHH基因的外显子和相邻内含子均无碱基改变。
(2)明确基因突变组(N=87)：CHD7基因突变16例(19.1%),FGF8有2例(2.2%), FGFR1有20例(22.5%),GNRHR有4例(4.5%),KALl有14例(15.7%),KISSIR有2例(2.2%),LEPRE有1例(1.1%),LHB有3例(3.4%),NELF有1例(1.1%),PROK2有4例(4.5%),PROKR2有19例(21.3%),WDR11有1例(1.1%)。CHD7、KAL1、FGFR1和PROKR2是主要的突变基因,占明确基因突变组的79%。
(3)在明确基因突变组(N=87)：三基因突变有2例(2.2%),双基因突变18例(20.7%),单基因突变67例(77.0%)。单基因突变和双(寡)基因突变组之间,初始睾丸体积、生精指数无显著性差异。
(4)在FGFR1、CHD7、KAL1和PROKR2突变导致IHH的四组患者中,FGFR1突变组的初始睾丸体积和生精指数显著低于其他三组。
(5)明确基因突变组(N=87)的生精指数显著低于可疑基因突变组(N=35)(0.99±0.08vs.1.47±0.14,P=0.003)和未检测到基因突变组(N=68)(0.99±0.08vs.1.37±0.10,P=0.003)。明确基因突变组的nIHH患者(N=31),生精指数显著低于未检测到基因突变组的nIHH患者(N=30)(1.09±0.13vs.1.70±0.10,P=0.0006)。而明确基因突变组的KS(N=56)的生精指数和未检测到基因突变组的KS(N=38)无显著性差异。
(6)根据基因型和临床嗅觉表型对IHH患者进行分类,生精指数从低到高分别是：FGFR1突变组 (7)无论在明确基因突变组内还是未检测到基因突变组内,nIHH患者的BMI均高于KS患者。在全部IHH患者中,nIHH人群BMI大于KS人群。
(8)不同基因突变和临床特异表现之间的相关性：有家族史的患者更易检出KAL1突变。FGFR1突变患者可有矮小、唇腭裂和牙齿发育异常。KAL1和CHD7突变均可发生单侧肾脏发育不良。
(9)有7例(2.7%)IHH患者的性腺轴功能发生逆转。其中KAL1基因突变2例,PROKR2和LHB突变各1例。其他3例未检测到基因突变。患者初诊年龄22.4±0.8岁,确定逆转的年龄为25.1±0.7岁；此人群的GnRHa(曲普瑞林)兴奋试验LH峰值为19.1±2.2(7.7-33IU/L),患者的初始睾丸体积为6.0±0.6mL。
[结论](1)约1/3的男性IHH患者可检测到明确致病基因。CHD7、FGFR1、PROK2和KAL1四个基因突变占全部突变约80%,其中FGFR1突变患者的性腺轴功能损伤最为严重。(2)在明确基因突变IHH患者中,23%的患者存在双(寡)基因突变,77%为单基因突变,两组患者的生精指数无显著性差异。(3)根据基因型和嗅觉差异对IHH患者进行分类,生精指数从低到高分别为FGFR1突变组Objective
The aims of our study were as followings:(1) To clarify the incidence of bigenic and monogenic mutations in Chinese male patients with IHH.(2) To investigate the relationship between genotype and phenotype in some IHH patients with known gene mutations.(3) To evaluate the influence of gene mutations and clinical features (anosmia) on gonadotropin induced spermatogenesis.(4)To explore the predictive factors (clinical features and gene mutations) for patients with reversed gonad axis function.
Methodes
(1) Molecular studies:A gene chip (NimbleGen2.1M) and high-throughput techniques were used to investigate the mutations in19IHH genes of male IHH patients. For each mutants, the possible SNPs or pathogenic role was evaluated by four data banks (dbSNP, Hapmap,1000genes, BGI local gene bank). The SIFT and Polyphen-2, two widely used computer simulated software, were used to predict the degree of impaired protein function. For the definite gene mutants, classical direct PCR method was used to confirm the results. The patients were classified into four groups according to their gene results:definite mutation group, suspected mutation group, invalid mutation group and no known mutation group.
(2) Clinical studies:the clinical data of IHH patients were collected from the medical records, including the age, testicular volumes, cryptorchid history, other secreted hormones from the pituitary gland, magnetic image of olfactory bulb and the effects of gonadotropin induced spermatogenesis. A spermatogenesis score system, including testicular volumns, testosterone levels responsing to HCG, sperm count and other important parameters, reflects the effets of gonadotropin induced spermatogenesis. The score was semiquantitatively defined as0,1,2and3. The higher the score, the greater capacity for sperm production.
(3) Data analysis:Unpaired t test were used to compare the difference between two groups comprising normal distributed continuous variable. Kruskal-Wallis was used to compare the difference between two groups comprising normal distributed uncontinuous categorical variables.
Results
(1) In our male IHH patients,87/259patients (33.6%) were found had known definit gene mutations. The percentage of suspected mutations, invalid mutations and no known mutations were13.5%,26.8%and26.2%, respectively. The percentage of definite gene mutations were as followings:CHD719.1%, FGF82.2%, FGFR122.5%, GNRHR4.5%, KAL115.7%, KISS1R2.2%, LEPRE1.1%, LHB3.4%, NELF1.1%, PROK24.5%, PROKR221.3%and WDR111.1%. No mutations were detected in DAX1, Leptin, FSHB, TACR3/TAC3, PCSK1and GNRH1. CHD7, FGFR1, KAL1and PROKR2dominated79%of all definite gene mutations.
(2) In patients with definite gene mutations, two patients (2.2%) had trigenic mutations,18(20.7%) had bigenic mutations, and67(77.0%) had monogenic mutations. No significant differences were found in the testicular volumns and gonadotropin induced spermatogenesis scores between oligo-and mono-genic mutation groups.(3) The patients with FGFR1mutation had higher incidence of cryptorchid, lower spermatogenesis score than patients with other gene mutations. Spermatogenesis score was lower in definite mutation group than suspected mutation group (0.99±0.08vs.1.47±0.14,P=0.003) and no known gene mutation group (0.99±0.08vs.1.37±0.10, P=0.003). Spermatogenesis score of nIHH from definite gene mutation group was lower than that from no known mutation group (1.09±0.13vs.1.70±0.10, P=0.0006), while the score of KS had no significant difference between gene mutation-positive group and no known mutation group. In general, the spermatogenesis score from the lowest to the highest were as followings:FGFR1mutation group (3) The patients with positive family histories have a tendency for KAL1mutation. The patients with FGFR1mutation may present with short status, plate clips and tooth aplasia. KAL1and CHD7mutation may cause unilateral renal dysplasia. However, these clinical features can also been seen in patients from no known mutation group.
(4) Seven IHH patients (2.7%) had reversal of gonad axis function. Among them, four patients had gene mutations in KALI (2patients), PROKR2(1patient) and LHB (1patient). The average diagnostic and reversal age was22.4±0.8and25.1±0.7years. Their GnRHa stimulated LH level was19.1±2.2(7.7-33mIU/ml) and their initial testicular volume was6.0±0.6mL.
Conclusions
(1) Causative gene mutations can be detected in about1/3of IHH male patients. CHD7, FGFR1, PROK2and KAL1dominated79%of all mutations.(2) In patients with definite gene mutations,23%of them were oligogenic mutations and77%were monogenic mutations. The spermatogenesis scores had no significant difference between these two groups.(3) According to the genotypes and olfactory manefestations, the spermatogenesis scores from the lowest to the hightest were as followings:FGFR1mutation group
(1)在中国男性特发性低促性腺激素性性腺功能减退症(IHH)患者中,明确基因突变的发生率是多少?各致病基因比重如何?
(2)不同基因所致IHH,各有何临床特点?这些临床特点,能否提示某种基因突变?
(3)有多少患者存在双(寡)基因突变?和单基因突变的患者相比,双(寡)基因突变的IHH患者,是否存在更严重的性腺轴功能损伤?
(4)根据基因检测和临床表现(有无嗅觉)对IHH患者进行亚组分析,评价不同患者人群的精子生成差异。
[方法]
(1)基因研究：采用基因芯片(NimbleGen2.1M基因芯片组),对IHH患者和部分家属的19个IHH基因外显子和相邻内含子进行检测。对每一个改变的碱基,通过多个数据库进行多态性分析或突变状态的检测。利用SIFT和Polyphen-2计算机模拟软件,对突变基因及其编码蛋白质的功能进行预测。对明确的基因突变检测结果,用经典sanger PCR方法进行验证。根据基因突变情况,把患者分为明确基因突变组、可疑基因突变组、无效基因突变组和未检测到基因突变组。
(2)临床研究：收集患者的临床资料,包括性别、年龄、初诊和随访中的睾丸体积、垂体前叶激素水平、生精治疗后的睾酮水平、睾丸体积、精子数量和爱人妊娠情况。根据睾丸体积和生精治疗的效果,对患者的精子生成能力进行半定量评分,分为0、1、2、3四个等级,称为“生精指数”。分数越高,提示生精治疗的效果越好,产生精子的可能性越大,精子数量越多。
(3)统计学方法：不同组之间的比较：对符合正态分布的连续性变量,采用非配对t检验；对符合正态分布的有序分类变量,采用Kruskal-Wallis检验。除非特殊说明,数据以平均值±标准误(Mean±SE)表示。
[结果]
(1)男性259例IHH患者中,明确基因突变87例(33.6%),可疑基因突变35例(13.5%),无效基因突变69例(26.8%),未检测到已知基因突变68例(26.2%)。明确基因突变是指,基因突变已被报道过,或已通过体外试验验证了功能缺陷,或发生于剪切位点的碱基改变,或通过计算机模拟软件(SIFT和Polyphen-2检测方法)提示蛋白质功能受到明显损害。可疑基因突变是指：发生率小于1%的SNP,或以常染色体隐性遗传方式的致病基因发生杂合突变(即两个等位基因中,有一个发生可导致氨基酸变化的突变)。无效基因突变是指,内含子(非剪切位点)存在异常或外显子发生同义突变。未检测到基因突变是指,IHH基因的外显子和相邻内含子均无碱基改变。
(2)明确基因突变组(N=87)：CHD7基因突变16例(19.1%),FGF8有2例(2.2%), FGFR1有20例(22.5%),GNRHR有4例(4.5%),KALl有14例(15.7%),KISSIR有2例(2.2%),LEPRE有1例(1.1%),LHB有3例(3.4%),NELF有1例(1.1%),PROK2有4例(4.5%),PROKR2有19例(21.3%),WDR11有1例(1.1%)。CHD7、KAL1、FGFR1和PROKR2是主要的突变基因,占明确基因突变组的79%。
(3)在明确基因突变组(N=87)：三基因突变有2例(2.2%),双基因突变18例(20.7%),单基因突变67例(77.0%)。单基因突变和双(寡)基因突变组之间,初始睾丸体积、生精指数无显著性差异。
(4)在FGFR1、CHD7、KAL1和PROKR2突变导致IHH的四组患者中,FGFR1突变组的初始睾丸体积和生精指数显著低于其他三组。
(5)明确基因突变组(N=87)的生精指数显著低于可疑基因突变组(N=35)(0.99±0.08vs.1.47±0.14,P=0.003)和未检测到基因突变组(N=68)(0.99±0.08vs.1.37±0.10,P=0.003)。明确基因突变组的nIHH患者(N=31),生精指数显著低于未检测到基因突变组的nIHH患者(N=30)(1.09±0.13vs.1.70±0.10,P=0.0006)。而明确基因突变组的KS(N=56)的生精指数和未检测到基因突变组的KS(N=38)无显著性差异。
(6)根据基因型和临床嗅觉表型对IHH患者进行分类,生精指数从低到高分别是：FGFR1突变组
(8)不同基因突变和临床特异表现之间的相关性：有家族史的患者更易检出KAL1突变。FGFR1突变患者可有矮小、唇腭裂和牙齿发育异常。KAL1和CHD7突变均可发生单侧肾脏发育不良。
(9)有7例(2.7%)IHH患者的性腺轴功能发生逆转。其中KAL1基因突变2例,PROKR2和LHB突变各1例。其他3例未检测到基因突变。患者初诊年龄22.4±0.8岁,确定逆转的年龄为25.1±0.7岁；此人群的GnRHa(曲普瑞林)兴奋试验LH峰值为19.1±2.2(7.7-33IU/L),患者的初始睾丸体积为6.0±0.6mL。
[结论](1)约1/3的男性IHH患者可检测到明确致病基因。CHD7、FGFR1、PROK2和KAL1四个基因突变占全部突变约80%,其中FGFR1突变患者的性腺轴功能损伤最为严重。(2)在明确基因突变IHH患者中,23%的患者存在双(寡)基因突变,77%为单基因突变,两组患者的生精指数无显著性差异。(3)根据基因型和嗅觉差异对IHH患者进行分类,生精指数从低到高分别为FGFR1突变组
The aims of our study were as followings:(1) To clarify the incidence of bigenic and monogenic mutations in Chinese male patients with IHH.(2) To investigate the relationship between genotype and phenotype in some IHH patients with known gene mutations.(3) To evaluate the influence of gene mutations and clinical features (anosmia) on gonadotropin induced spermatogenesis.(4)To explore the predictive factors (clinical features and gene mutations) for patients with reversed gonad axis function.
Methodes
(1) Molecular studies:A gene chip (NimbleGen2.1M) and high-throughput techniques were used to investigate the mutations in19IHH genes of male IHH patients. For each mutants, the possible SNPs or pathogenic role was evaluated by four data banks (dbSNP, Hapmap,1000genes, BGI local gene bank). The SIFT and Polyphen-2, two widely used computer simulated software, were used to predict the degree of impaired protein function. For the definite gene mutants, classical direct PCR method was used to confirm the results. The patients were classified into four groups according to their gene results:definite mutation group, suspected mutation group, invalid mutation group and no known mutation group.
(2) Clinical studies:the clinical data of IHH patients were collected from the medical records, including the age, testicular volumes, cryptorchid history, other secreted hormones from the pituitary gland, magnetic image of olfactory bulb and the effects of gonadotropin induced spermatogenesis. A spermatogenesis score system, including testicular volumns, testosterone levels responsing to HCG, sperm count and other important parameters, reflects the effets of gonadotropin induced spermatogenesis. The score was semiquantitatively defined as0,1,2and3. The higher the score, the greater capacity for sperm production.
(3) Data analysis:Unpaired t test were used to compare the difference between two groups comprising normal distributed continuous variable. Kruskal-Wallis was used to compare the difference between two groups comprising normal distributed uncontinuous categorical variables.
Results
(1) In our male IHH patients,87/259patients (33.6%) were found had known definit gene mutations. The percentage of suspected mutations, invalid mutations and no known mutations were13.5%,26.8%and26.2%, respectively. The percentage of definite gene mutations were as followings:CHD719.1%, FGF82.2%, FGFR122.5%, GNRHR4.5%, KAL115.7%, KISS1R2.2%, LEPRE1.1%, LHB3.4%, NELF1.1%, PROK24.5%, PROKR221.3%and WDR111.1%. No mutations were detected in DAX1, Leptin, FSHB, TACR3/TAC3, PCSK1and GNRH1. CHD7, FGFR1, KAL1and PROKR2dominated79%of all definite gene mutations.
(2) In patients with definite gene mutations, two patients (2.2%) had trigenic mutations,18(20.7%) had bigenic mutations, and67(77.0%) had monogenic mutations. No significant differences were found in the testicular volumns and gonadotropin induced spermatogenesis scores between oligo-and mono-genic mutation groups.(3) The patients with FGFR1mutation had higher incidence of cryptorchid, lower spermatogenesis score than patients with other gene mutations. Spermatogenesis score was lower in definite mutation group than suspected mutation group (0.99±0.08vs.1.47±0.14,P=0.003) and no known gene mutation group (0.99±0.08vs.1.37±0.10, P=0.003). Spermatogenesis score of nIHH from definite gene mutation group was lower than that from no known mutation group (1.09±0.13vs.1.70±0.10, P=0.0006), while the score of KS had no significant difference between gene mutation-positive group and no known mutation group. In general, the spermatogenesis score from the lowest to the highest were as followings:FGFR1mutation group
(4) Seven IHH patients (2.7%) had reversal of gonad axis function. Among them, four patients had gene mutations in KALI (2patients), PROKR2(1patient) and LHB (1patient). The average diagnostic and reversal age was22.4±0.8and25.1±0.7years. Their GnRHa stimulated LH level was19.1±2.2(7.7-33mIU/ml) and their initial testicular volume was6.0±0.6mL.
Conclusions
(1) Causative gene mutations can be detected in about1/3of IHH male patients. CHD7, FGFR1, PROK2and KAL1dominated79%of all mutations.(2) In patients with definite gene mutations,23%of them were oligogenic mutations and77%were monogenic mutations. The spermatogenesis scores had no significant difference between these two groups.(3) According to the genotypes and olfactory manefestations, the spermatogenesis scores from the lowest to the hightest were as followings:FGFR1mutation group
引文
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6. Stark Z, Storen R, Bennetts B, Savarirayan R, Jamieson RV:Isolated hypogonadotropic hypogonadism with SOX2 mutation and anophthalmia/microphthalmia in offspring. Eur J Hum Genet 2011,19:753-756.
7. Hanchate NK, Giacobini P, Lhuillier P, Parkash J, Espy C, Fouveaut C, Leroy C, Baron S, Campagne C, Vanacker C, et al:SEMA3A, a gene involved in axonal pathfinding, is mutated in patients with Kallmann syndrome. PLoS Genet 2012,8:e1002896.
8. Mitchell AL, Dwyer A, Pitteloud N, Quinton R:Genetic basis and variable phenotypic expression of Kallmann syndrome:towards a unifying theory. Trends Endocrinol Metab 2011,22:249-258.
9. Quaynor SD, Kim HG, Cappello EM, Williams T, Chorich LP, Bick DP, Sherins RJ, Layman LC:The prevalence of digenic mutations in patients with normosmic hypogonadotropic hypogonadism and Kallmann syndrome. Fertil Steril 2011,96:1424-1430 e1426.
10. Pitteloud N, Acierno JS, Jr., Meysing AU, Dwyer AA, Hayes FJ, Crowley WF, Jr.:Reversible kallmann syndrome, delayed puberty, and isolated anosmia occurring in a single family with a mutation in the fibroblast growth factor receptor 1 gene. JClin Endocrinol Metab 2005,90:1317-1322.
11. Caronia LM, Martin C, Welt CK, Sykiotis GP, Quinton R, Thambundit A, Avbelj M, Dhruvakumar S, Plummer L, Hughes VA, et al:A genetic basis for functional hypothalamic amenorrhea. N Engl J Med 2011,364:215-225.
12. Pitteloud N, Durrani S, Raivio T, Sykiotis GP:Complex genetics in idiopathic hypogonadotropic hypogonadism. Front Horm Res 2010,39:142-153.
13. Ribeiro RS, Vieira TC, Abucham J:Reversible Kallmann syndrome:report of the first case with a KAL1 mutation and literature review. Eur J Endocrinol 2007,156:285-290.
14. Root AW:Reversible isolated hypogonadotropic hypogonadism due to mutations in the neurokinin B regulation of gonadotropin-releasing hormone release. J Clin Endocrinol Metab 2010,95:2625-2629.
15. Sinisi AA, Asci R, Bellastella G, Maione L, Esposito D, Elefante A, De Bellis A, Bellastella A, Iolascon A:Homozygous mutation in the prokineticin-receptor2 gene (Val274Asp) presenting as reversible Kallmann syndrome and persistent oligozoospermia:case report. Hum Reprod 2008,23:2380-2384.
16. Chevrier L, Guimiot F, de Roux N:GnRH receptor mutations in isolated gonadotropic deficiency. Mol Cell Endocrinol 2011,346:21-28.
17. Sykiotis GP, Hoang XH, Avbelj M, Hayes FJ, Thambundit A, Dwyer A, Au M, Plummer L, Crowley WF, Jr., Pitteloud N:Congenital idiopathic hypogonadotropic hypogonadism: evidence of defects in the hypothalamus, pituitary, and testes. J Clin Endocrinol Metab 2010,95:3019-3027.
18. Warne DW, Decosterd G, Okada H, Yano Y, Koide N, Howles CM:A combined analysis of data to identify predictive factors for spermatogenesis in men with hypogonadotropic hypogonadism treated with recombinant human follicle-stimulating hormone and human chorionic gonadotropin. Fertil Steril 2009,92:594-604.
19. Matsumoto AM, Snyder PJ, Bhasin S, Martin K, Weber T, Winters S, Spratt D, Brentzel J, O'Dea L:Stimulation of spermatogenesis with recombinant human follicle-stimulating hormone (follitropin alfa; GONAL-f):long-term treatment in azoospermic men with hypogonadotropic hypogonadism. Fertil Steril 2009,92:979-990.
20. Hadziselimovic NO, de Geyter C, Demougin P, Oakeley EJ, Hadziselimovic F:Decreased expression of FGFR1, SOS1, RAF1 genes in cryptorchidism. Urol Int 2010,84:353-361.
21. Li Y, Vinckenbosch N, Tian G, Huerta-Sanchez E, Jiang T, Jiang H, Albrechtsen A, Andersen G, Cao H, Korneliussen T, et al:Resequencing of 200 human exomes identifies an excess of low-frequency non-synonymous coding variants. Nat Genet 2010,42:969-972.
22. Choi M, Scholl UI, Ji W, Liu T, Tikhonova IR, Zumbo P, Nayir A, Bakkaloglu A, Ozen S, Sanjad S, et al:Genetic diagnosis by whole exome capture and massively parallel DNA sequencing. Proc Natl Acad Sci USA 2009,106:19096-19101.
23. Jaffe A, Wojcik G, Chu A, Golozar A, Maroo A, Duggal P, Klein AP:Identification of functional genetic variation in exome sequence analysis. BMC Proc 2011,5 Suppl 9:S13.
24. Wei P, Liu X, Fu YX:Incorporating predicted functions of nonsynonymous variants into gene-based analysis of exome sequencing data:a comparative study. BMC Proc 2011,5 Suppl 9:S20.
25. Lopes MC, Joyce C, Ritchie GR, John SL, Cunningham F, Asimit J, Zeggini E:A combined functional annotation score for non-synonymous variants. Hum Hered 2012,73:47-51.
26. Gray VE, Kukurba KR, Kumar S:Performance of computational tools in evaluating the functional impact of laboratory-induced amino acid mutations. Bioinformatics 2012, 28:2093-2096.
27. Balasubramanian R, Crowley WF, Jr.:Isolated GnRH deficiency:a disease model serving as a unique prism into the systems biology of the GnRH neuronal network. Mol Cell Endocrinol 2011,346:4-12.
28. Gurbuz F, Kotan LD, Mengen E, Siklar Z, Berberoglu M, Dokmetas S, Kilicli MF, Guven A, Kirel B, Saka N, et al:Distribution of Gene Mutations Associated with Familial Normosmic Idiopathic Hypogonadotropic Hypogonadism. J Clin Res Pediatr Endocrinol 2012.
29. Sykiotis GP, Plummer L, Hughes VA, Au M, Durrani S, Nayak-Young S, Dwyer AA, Quinton R, Hall JE, Gusella JF, et al:Oligogenic basis of isolated gonadotropin-releasing hormone deficiency. Proc Natl Acad Sci U S A 2010,107:15140-15144.
30. Laitinen EM, Vaaralahti K, Tommiska J, Eklund E, Tervaniemi M, Valanne L, Raivio T: Incidence, phenotypic features and molecular genetics of Kallmann syndrome in Finland. Orphanet J Rare Dis 2011,6:41.
31. Topaloglu AK, Kotan LD:Molecular causes of hypogonadotropic hypogonadism. Curr Opin Obstet Gynecol 2010,22:264-270.
32. Pitteloud N, Boepple PA, DeCruz S, Valkenburgh SB, Crowley WF, Jr., Hayes FJ:The fertile eunuch variant of idiopathic hypogonadotropic hypogonadism:spontaneous reversal associated with a homozygous mutation in the gonadotropin-releasing hormone receptor. J Clin Endocrinol Metab 2001,86:2470-2475.
33. Miyagawa Y, Tsujimura A, Matsumiya K, Takao T, Tohda A, Koga M, Takeyama M, Fujioka H, Takada S, Koide T, Okuyama A:Outcome of gonadotropin therapy for male hypogonadotropic hypogonadism at university affiliated male infertility centers:a 30-year retrospective study. J Urol 2005,173:2072-2075.
34. Burris AS, Rodbard HW, Winters SJ, Sherins RJ:Gonadotropin therapy in men with isolated hypogonadotropic hypogonadism:the response to human chorionic gonadotropin is predicted by initial testicular size. J Clin Endocrinol Metab 1988, 66:1144-1151.
35. Cooper TG, Noonan E, von Eckardstein S, Auger J, Baker HW, Behre HM, Haugen TB, Kruger T, Wang C, Mbizvo MT, Vogelsong KM:World Health Organization reference values for human semen characteristics. Hum Reprod Update 2010,16:231-245.
36. Hu Y, Guimond SE, Travers P, Cadman S, Hohenester E, Turnbull JE, Kim SH, Bouloux PM: Novel mechanisms of fibroblast growth factor receptor 1 regulation by extracellular matrix protein anosmin-1. J Biol Chem 2009,284:29905-29920.
37. Ayari B, Soussi-Yanicostas N:FGFR1 and anosmin-1 underlying genetically distinct forms of Kallmann syndrome are co-expressed and interact in olfactory bulbs. Dev Genes Evol2007,217:169-175.
38. Kumar PA, Pitteloud N, Andrews PA, Dwyer A, Hayes F, Crowley WF, Jr., Dym M:Testis morphology in patients with idiopathic hypogonadotropic hypogonadism. Hum Reprod 2006,21:1033-1040.
39. Nishio H, Mizuno K, Moritoki Y, Kamisawa H, Kojima Y, Mizuno H, Kohri K, Hayashi Y: Clinical features and testicular morphology in patients with Kallmann syndrome. Urology 2012,79:684-686.
40. Bouvattier C, Maione L, Bouligand J, Dode C, Guiochon-Mantel A, Young J:Neonatal gonadotropin therapy in male congenital hypogonadotropic hypogonadism. Nat Rev Endocrinol 2012,8:172-182.
41. Salenave S, Chanson P, Bry H, Pugeat M, Cabrol S, Carel JC, Murat A, Lecomte P, Brailly S, Hardelin JP, et al:Kallmann's syndrome:a comparison of the reproductive phenotypes in men carrying KAL1 and FGFR1/KAL2 mutations. J Clin Endocrinol Metab 2008, 93:758-763.
42. Pitteloud N, Meysing A, Quinton R, Acierno JS, Jr., Dwyer AA, Plummer L, Fliers E, Boepple P, Hayes F, Seminara S, et al:Mutations in fibroblast growth factor receptor 1 cause Kallmann syndrome with a wide spectrum of reproductive phenotypes. Mol Cell Endocrinol 2006,254-255:60-69.
43. Raivio T, Sidis Y, Plummer L, Chen H, Ma J, Mukherjee A, Jacobson-Dickman E, Quinton R, Van Vliet G, Lavoie H, et al:Impaired fibroblast growth factor receptor 1 signaling as a cause of normosmic idiopathic hypogonadotropic hypogonadism. J Clin Endocrinol Metab 2009,94:4380-4390.
44. Wu XY, Mao JF, Lu SY, Zhang Q, Shi YF:Testosterone replacement therapy improves insulin sensitivity and decreases high sensitivity C-reactive protein levels in hypogonadotropic hypogonadal young male patients. Chin Med J (Engl) 2009, 122:2846-2850.
45. Singh SK, Goyal R, Pratyush DD:Is hypoandrogenemia a component of metabolic syndrome in males? Exp Clin Endocrinol Diabetes 2011,119:30-35.
46. Sonmez A, Haymana C, Bolu E, Aydogdu A, Tapan S, Serdar M, Altun B, Barcin C, Taslipinar A, Meric C, et al:Metabolic syndrome and the effect of testosterone treatment in young men with congenital hypogonadotropic hypogonadism. Eur J Endocrinol 2011, 164:759-764.
47. Corona G, Rastrelli G, Morelli A, Vignozzi L, Mannucci E, Maggi M:Hypogonadism and metabolic syndrome. J Endocrinol Invest 2011,34:557-567.
48. Fukui M, Kitagawa Y, Ose H, Hasegawa G, Yoshikawa T, Nakamura N:Role of endogenous androgen against insulin resistance and athero-sclerosis in men with type 2 diabetes. Curr Diabetes Rev 2007,3:25-31.
49. Kapoor D, Jones TH:Androgen deficiency as a predictor of metabolic syndrome in aging men:an opportunity for intervention? Drugs Aging 2008,25:357-369.
50. Cole LW, Sidis Y, Zhang C, Quinton R, Plummer L, Pignatelli D, Hughes VA, Dwyer AA, Raivio T, Hayes FJ, et al:Mutations in prokineticin 2 and prokineticin receptor 2 genes in human gonadotrophin-releasing hormone deficiency:molecular genetics and clinical spectrum. JClin Endocrinol Metab 2008,93:3551-3559.
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19. de Roux N, Genin E, Carel JC, et al. Hypogonadotropic hypogonadism due to loss of function of the KiSS 1-derived peptide receptor GPR54. Proc Natl Acad Sci USA,2003,100, 10972-10976.
20. Lanfranco F, Gromoll J, von Eckardstein S, et al. Role of sequence variations of the GnRH receptor and G protein-coupled receptor 54 gene in male idiopathic hypogonadotropic hypogonadism. Eur J Endocrinol,2005,153,845-852.
21. Topaloglu A, Reimann F, Guclu M, et al. TAC3 and TACR3 mutations in familial hypogonadotropic hypogonadism reveal a key role for Neurokinin B in the central control of reproduction. Nat Genet,2009,41,354-358.
22. Guran T, Tolhurst G, Bereket A, et al. A Novel Missense Mutation in the First Extracellular Loop of the Neurokinin B Receptor Causes Hypogonadotropic Hypogonadism. J Clin Endoc Metab,2009,94(10):3633-9.
23. Rance NE Menopause and the human hypothalamus:Evidence for the role of kisspeptin/neurokinin B neurons in the regulation of estrogen negative feedback. Peptides. 2008,30(1),111-122
24. Sandoval GT, Rance NE. Central injection of senktide, an NK3 receptor agonist, or neuropeptide Y inhibits LH secretion and induces different patterns of Fos expression in the rat hypothalamus. Brain Res,2004,1026,307-312.
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26. Salenave S, Chanson P, Bry H, et al. Kallmann's syndrome:a comparison of the reproductive phenotypes in men carrying KAL1 and FGFR1/KAL2 mutations. J Clin Endocrinol Metab, 2008,93,758-763.
2. Raivio T, Falardeau J, Dwyer A, Quinton R, Hayes FJ, Hughes VA3 Cole LW, Pearce SH, Lee H, Boepple P, et al:Reversal of idiopathic hypogonadotropic hypogonadism. N Engl J Med 2007,357:863-873.
3. Laitinen E-M, Tommiska J, Sane T, Vaaralahti K, Toppari J, Raivio T:Reversible Congenital Hypogonadotropic Hypogonadism in Patients with CHD7, FGFR1 or GNRHR Mutations. PLoS ONE 2012,7.
4. Bonomi M, Libri DV, Guizzardi F, Guarducci E, Maiolo E, Pignatti E, Asci R, Persani L:New understandings of the genetic basis of isolated idiopathic central hypogonadism. Asian J Androl 2012,14:49-56.
5. Tornberg J, Sykiotis GP, Keefe K, Plummer L, Hoang X, Hall JE, Quinton R, Seminara SB, Hughes V, Van Vliet G, et al:Heparan sulfate 6-O-sulfotransferase 1, a gene involved in extracellular sugar modifications, is mutated in patients with idiopathic hypogonadotrophic hypogonadism. Proc Natl Acad Sci USA 2011,108:11524-11529.
6. Stark Z, Storen R, Bennetts B, Savarirayan R, Jamieson RV:Isolated hypogonadotropic hypogonadism with SOX2 mutation and anophthalmia/microphthalmia in offspring. Eur J Hum Genet 2011,19:753-756.
7. Hanchate NK, Giacobini P, Lhuillier P, Parkash J, Espy C, Fouveaut C, Leroy C, Baron S, Campagne C, Vanacker C, et al:SEMA3A, a gene involved in axonal pathfinding, is mutated in patients with Kallmann syndrome. PLoS Genet 2012,8:e1002896.
8. Mitchell AL, Dwyer A, Pitteloud N, Quinton R:Genetic basis and variable phenotypic expression of Kallmann syndrome:towards a unifying theory. Trends Endocrinol Metab 2011,22:249-258.
9. Quaynor SD, Kim HG, Cappello EM, Williams T, Chorich LP, Bick DP, Sherins RJ, Layman LC:The prevalence of digenic mutations in patients with normosmic hypogonadotropic hypogonadism and Kallmann syndrome. Fertil Steril 2011,96:1424-1430 e1426.
10. Pitteloud N, Acierno JS, Jr., Meysing AU, Dwyer AA, Hayes FJ, Crowley WF, Jr.:Reversible kallmann syndrome, delayed puberty, and isolated anosmia occurring in a single family with a mutation in the fibroblast growth factor receptor 1 gene. JClin Endocrinol Metab 2005,90:1317-1322.
11. Caronia LM, Martin C, Welt CK, Sykiotis GP, Quinton R, Thambundit A, Avbelj M, Dhruvakumar S, Plummer L, Hughes VA, et al:A genetic basis for functional hypothalamic amenorrhea. N Engl J Med 2011,364:215-225.
12. Pitteloud N, Durrani S, Raivio T, Sykiotis GP:Complex genetics in idiopathic hypogonadotropic hypogonadism. Front Horm Res 2010,39:142-153.
13. Ribeiro RS, Vieira TC, Abucham J:Reversible Kallmann syndrome:report of the first case with a KAL1 mutation and literature review. Eur J Endocrinol 2007,156:285-290.
14. Root AW:Reversible isolated hypogonadotropic hypogonadism due to mutations in the neurokinin B regulation of gonadotropin-releasing hormone release. J Clin Endocrinol Metab 2010,95:2625-2629.
15. Sinisi AA, Asci R, Bellastella G, Maione L, Esposito D, Elefante A, De Bellis A, Bellastella A, Iolascon A:Homozygous mutation in the prokineticin-receptor2 gene (Val274Asp) presenting as reversible Kallmann syndrome and persistent oligozoospermia:case report. Hum Reprod 2008,23:2380-2384.
16. Chevrier L, Guimiot F, de Roux N:GnRH receptor mutations in isolated gonadotropic deficiency. Mol Cell Endocrinol 2011,346:21-28.
17. Sykiotis GP, Hoang XH, Avbelj M, Hayes FJ, Thambundit A, Dwyer A, Au M, Plummer L, Crowley WF, Jr., Pitteloud N:Congenital idiopathic hypogonadotropic hypogonadism: evidence of defects in the hypothalamus, pituitary, and testes. J Clin Endocrinol Metab 2010,95:3019-3027.
18. Warne DW, Decosterd G, Okada H, Yano Y, Koide N, Howles CM:A combined analysis of data to identify predictive factors for spermatogenesis in men with hypogonadotropic hypogonadism treated with recombinant human follicle-stimulating hormone and human chorionic gonadotropin. Fertil Steril 2009,92:594-604.
19. Matsumoto AM, Snyder PJ, Bhasin S, Martin K, Weber T, Winters S, Spratt D, Brentzel J, O'Dea L:Stimulation of spermatogenesis with recombinant human follicle-stimulating hormone (follitropin alfa; GONAL-f):long-term treatment in azoospermic men with hypogonadotropic hypogonadism. Fertil Steril 2009,92:979-990.
20. Hadziselimovic NO, de Geyter C, Demougin P, Oakeley EJ, Hadziselimovic F:Decreased expression of FGFR1, SOS1, RAF1 genes in cryptorchidism. Urol Int 2010,84:353-361.
21. Li Y, Vinckenbosch N, Tian G, Huerta-Sanchez E, Jiang T, Jiang H, Albrechtsen A, Andersen G, Cao H, Korneliussen T, et al:Resequencing of 200 human exomes identifies an excess of low-frequency non-synonymous coding variants. Nat Genet 2010,42:969-972.
22. Choi M, Scholl UI, Ji W, Liu T, Tikhonova IR, Zumbo P, Nayir A, Bakkaloglu A, Ozen S, Sanjad S, et al:Genetic diagnosis by whole exome capture and massively parallel DNA sequencing. Proc Natl Acad Sci USA 2009,106:19096-19101.
23. Jaffe A, Wojcik G, Chu A, Golozar A, Maroo A, Duggal P, Klein AP:Identification of functional genetic variation in exome sequence analysis. BMC Proc 2011,5 Suppl 9:S13.
24. Wei P, Liu X, Fu YX:Incorporating predicted functions of nonsynonymous variants into gene-based analysis of exome sequencing data:a comparative study. BMC Proc 2011,5 Suppl 9:S20.
25. Lopes MC, Joyce C, Ritchie GR, John SL, Cunningham F, Asimit J, Zeggini E:A combined functional annotation score for non-synonymous variants. Hum Hered 2012,73:47-51.
26. Gray VE, Kukurba KR, Kumar S:Performance of computational tools in evaluating the functional impact of laboratory-induced amino acid mutations. Bioinformatics 2012, 28:2093-2096.
27. Balasubramanian R, Crowley WF, Jr.:Isolated GnRH deficiency:a disease model serving as a unique prism into the systems biology of the GnRH neuronal network. Mol Cell Endocrinol 2011,346:4-12.
28. Gurbuz F, Kotan LD, Mengen E, Siklar Z, Berberoglu M, Dokmetas S, Kilicli MF, Guven A, Kirel B, Saka N, et al:Distribution of Gene Mutations Associated with Familial Normosmic Idiopathic Hypogonadotropic Hypogonadism. J Clin Res Pediatr Endocrinol 2012.
29. Sykiotis GP, Plummer L, Hughes VA, Au M, Durrani S, Nayak-Young S, Dwyer AA, Quinton R, Hall JE, Gusella JF, et al:Oligogenic basis of isolated gonadotropin-releasing hormone deficiency. Proc Natl Acad Sci U S A 2010,107:15140-15144.
30. Laitinen EM, Vaaralahti K, Tommiska J, Eklund E, Tervaniemi M, Valanne L, Raivio T: Incidence, phenotypic features and molecular genetics of Kallmann syndrome in Finland. Orphanet J Rare Dis 2011,6:41.
31. Topaloglu AK, Kotan LD:Molecular causes of hypogonadotropic hypogonadism. Curr Opin Obstet Gynecol 2010,22:264-270.
32. Pitteloud N, Boepple PA, DeCruz S, Valkenburgh SB, Crowley WF, Jr., Hayes FJ:The fertile eunuch variant of idiopathic hypogonadotropic hypogonadism:spontaneous reversal associated with a homozygous mutation in the gonadotropin-releasing hormone receptor. J Clin Endocrinol Metab 2001,86:2470-2475.
33. Miyagawa Y, Tsujimura A, Matsumiya K, Takao T, Tohda A, Koga M, Takeyama M, Fujioka H, Takada S, Koide T, Okuyama A:Outcome of gonadotropin therapy for male hypogonadotropic hypogonadism at university affiliated male infertility centers:a 30-year retrospective study. J Urol 2005,173:2072-2075.
34. Burris AS, Rodbard HW, Winters SJ, Sherins RJ:Gonadotropin therapy in men with isolated hypogonadotropic hypogonadism:the response to human chorionic gonadotropin is predicted by initial testicular size. J Clin Endocrinol Metab 1988, 66:1144-1151.
35. Cooper TG, Noonan E, von Eckardstein S, Auger J, Baker HW, Behre HM, Haugen TB, Kruger T, Wang C, Mbizvo MT, Vogelsong KM:World Health Organization reference values for human semen characteristics. Hum Reprod Update 2010,16:231-245.
36. Hu Y, Guimond SE, Travers P, Cadman S, Hohenester E, Turnbull JE, Kim SH, Bouloux PM: Novel mechanisms of fibroblast growth factor receptor 1 regulation by extracellular matrix protein anosmin-1. J Biol Chem 2009,284:29905-29920.
37. Ayari B, Soussi-Yanicostas N:FGFR1 and anosmin-1 underlying genetically distinct forms of Kallmann syndrome are co-expressed and interact in olfactory bulbs. Dev Genes Evol2007,217:169-175.
38. Kumar PA, Pitteloud N, Andrews PA, Dwyer A, Hayes F, Crowley WF, Jr., Dym M:Testis morphology in patients with idiopathic hypogonadotropic hypogonadism. Hum Reprod 2006,21:1033-1040.
39. Nishio H, Mizuno K, Moritoki Y, Kamisawa H, Kojima Y, Mizuno H, Kohri K, Hayashi Y: Clinical features and testicular morphology in patients with Kallmann syndrome. Urology 2012,79:684-686.
40. Bouvattier C, Maione L, Bouligand J, Dode C, Guiochon-Mantel A, Young J:Neonatal gonadotropin therapy in male congenital hypogonadotropic hypogonadism. Nat Rev Endocrinol 2012,8:172-182.
41. Salenave S, Chanson P, Bry H, Pugeat M, Cabrol S, Carel JC, Murat A, Lecomte P, Brailly S, Hardelin JP, et al:Kallmann's syndrome:a comparison of the reproductive phenotypes in men carrying KAL1 and FGFR1/KAL2 mutations. J Clin Endocrinol Metab 2008, 93:758-763.
42. Pitteloud N, Meysing A, Quinton R, Acierno JS, Jr., Dwyer AA, Plummer L, Fliers E, Boepple P, Hayes F, Seminara S, et al:Mutations in fibroblast growth factor receptor 1 cause Kallmann syndrome with a wide spectrum of reproductive phenotypes. Mol Cell Endocrinol 2006,254-255:60-69.
43. Raivio T, Sidis Y, Plummer L, Chen H, Ma J, Mukherjee A, Jacobson-Dickman E, Quinton R, Van Vliet G, Lavoie H, et al:Impaired fibroblast growth factor receptor 1 signaling as a cause of normosmic idiopathic hypogonadotropic hypogonadism. J Clin Endocrinol Metab 2009,94:4380-4390.
44. Wu XY, Mao JF, Lu SY, Zhang Q, Shi YF:Testosterone replacement therapy improves insulin sensitivity and decreases high sensitivity C-reactive protein levels in hypogonadotropic hypogonadal young male patients. Chin Med J (Engl) 2009, 122:2846-2850.
45. Singh SK, Goyal R, Pratyush DD:Is hypoandrogenemia a component of metabolic syndrome in males? Exp Clin Endocrinol Diabetes 2011,119:30-35.
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