Pitteloud Nelly, Meysing Astrid, Quinton Richard, Acierno James S, Dwyer Andrew A, Plummer Lacey, Fliers Eric, Boepple Paul, Hayes Frances, Seminara Stephanie, Hughes Viriginia A, Ma Jinghong, Bouloux Pierre, Mohammadi Moosa, Crowley William F
Reproductive Endocrine Unit of the Department of Medicine & National Center for Infertility Research, Bartlett Hall Extension 5, Massachusetts General Hospital, 55 Fruit St., Boston, MA 02114, United States.
Mol Cell Endocrinol. 2006 Jul 25;254-255:60-9. doi: 10.1016/j.mce.2006.04.021. Epub 2006 Jun 9.
Kallmann's syndrome (KS) is a clinically and genetically heterogeneous disorder consisting of idiopathic hypogonadotropic hypogonadism (IHH) and anosmia. Mutations in KAL1 causing the X-linked form of KS have been identified in 10% of all KS patients and consistently result in a severe reproductive phenotype. KAL1 gene encodes for anosmin-1, a key protein involved in olfactory and GnRH neuronal migration through a putative interaction with FGFR1. Heterozygous mutations in the FGFR1 gene accompanied by a high frequency of cleft palate and other facial dysmorphisms were recently identified in 8% of a large KS cohort, yet the reproductive phenotype of KS patients harboring FGFR1 mutations has not been described.
One hundred and fifty probands with KS (130 males and 20 females) were studied to determine the frequency and distribution of FGFR1 mutations and their detailed reproductive phenotypes. Fifteen heterozygous mutations in unrelated probands were identified. Twelve missense mutations (p.R78C, p.V102I, p.D224H, p.G237D, p.R254Q, p.V273M, p.E274G, p.Y339C, p.S346C, p.I538V, p.G703S and p.G703R) were distributed among the first, second and third immunoglobulin-like domains (D1-D3), as well as the tyrosine kinase domain (TKD). The mutations Y339C and S346C are located in exon 8B and code for the isoform FGFR1c. Additionally, two nonsense mutations (p.T585X and p.R622X) were documented in the TKD of the protein. A wide spectrum of reproductive function was observed among KS probands including: (1) a severe phenotype demonstrated by microphallus, cryptorchidism, no pubertal development, undetectable serum gonadotropins and low serum testosterone (T) and inhibin B; (2) partial pubertal development; (3) the fertile eunuch variant of IHH with normal testicular size and active spermatogenesis with a reversal of HH after T therapy. In addition, we found an even wider spectrum of reproductive function within pedigrees carrying an FGFR1 mutation ranging from IHH to delayed puberty to normal reproductive function (anosmia only or asymptomatic carriers). These observations strongly suggest a role for other genes that modify the phenotype of FGFR1 mutations.
KS patients and family members carrying an FGFR1 mutation present a broad spectrum of pubertal development in contrast to the almost uniform severe clinical phenotype described in KS subjects with a KAL1 mutation. Additionally, this report implicates the isoform FGFR1c in the pathogenesis of KS.
卡尔曼综合征（KS）是一种临床和遗传异质性疾病，由特发性低促性腺激素性性腺功能减退（IHH）和嗅觉缺失组成。在所有KS患者中，10%已鉴定出导致X连锁型KS的KAL1基因突变，且这些突变始终导致严重的生殖表型。KAL1基因编码anosmin-1，这是一种通过与FGFR1的假定相互作用参与嗅觉和促性腺激素释放激素（GnRH）神经元迁移的关键蛋白。最近在一个大型KS队列的8%中鉴定出FGFR1基因的杂合突变，同时伴有高频率的腭裂和其他面部畸形，但携带FGFR1突变的KS患者的生殖表型尚未被描述。
对150例KS先证者（130例男性和20例女性）进行研究，以确定FGFR1突变的频率和分布及其详细的生殖表型。在无关先证者中鉴定出15个杂合突变。12个错义突变（p.R78C、p.V102I、p.D224H、p.G237D、p.R254Q、p.V273M、p.E274G、p.Y339C、p.S346C、p.I538V、p.G703S和p.G703R）分布在第一、第二和第三免疫球蛋白样结构域（D1-D3）以及酪氨酸激酶结构域（TKD）中。Y339C和S346C突变位于外显子8B中，编码异构体FGFR1c。此外，在该蛋白的TKD中记录到两个无义突变（p.T585X和p.R622X）。在KS先证者中观察到广泛的生殖功能，包括：（1）由小阴茎、隐睾、无青春期发育、无法检测到血清促性腺激素以及低血清睾酮（T）和抑制素B所表现出的严重表型；（2）部分青春期发育；（3）IHH的可育宦官变体，睾丸大小正常且精子发生活跃，T治疗后HH逆转。此外，我们发现在携带FGFR1突变的家系中，生殖功能范围更广，从IHH到青春期延迟再到正常生殖功能（仅嗅觉缺失或无症状携带者）。这些观察结果强烈表明其他基因在修饰FGFR1突变表型中起作用。
与携带KAL1突变的KS患者中几乎一致的严重临床表型相比，携带FGFR1突变的KS患者及其家庭成员呈现出广泛的青春期发育谱。此外，本报告表明异构体FGFR1c在KS的发病机制中起作用。
