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The inherited basis of hypergonadotropic hypogonadism
Published in Philip E. Harris, Pierre-Marc G. Bouloux, Endocrinology in Clinical Practice, 2014
Both FGFR1 and anosmin 1 represent separate though interacting genes involved in GnRH neuronal migration to the hypothalamus. Although loss-of-function mutations in FGFR1 and KAL1 can present with very similar phenotypes, FGFR1-related phenotypes are highly variable, with patients having both normosmic or anosmic forms of HH; indeed females with anosmia and normal reproductive function have been described with FGFR1 mutations.55,56 Moreover, reversal of GnRH deficiency has even been reported in some male patients with FGFR1 mutations after therapy with testosterone.
Scientific Basis of Male Hypogonadism
Published in Anthony R. Mundy, John M. Fitzpatrick, David E. Neal, Nicholas J. R. George, The Scientific Basis of Urology, 2010
Thang S. Han, Pierre-Marc G. Bouloux
The KALIG-1 gene encodes anosmin 1, a cell adhesion protein involved in the coordinated migration of GnRH-producing neurons and olfactory neurons. Born in the nasal pit, GnRH neurons migrate to the hypothalamus during early fetal development under the influence of anosmin 1. This process is impaired in KS because of inactivating mutations of the KALIG-1 gene (21). The concurrent underdeveloped olfactory tract can be identified by magnetic resonance imaging (MRI) scanning (22). Manifestations of X-linked KS include bimanual synkinesis and unilateral renal agenesis. Other defects such as cerebellar dysfunction, cleft palate, and congenital deafness may also be present in autosomal dominant forms of KS because of mutations of FGFR1. Recent studies have revealed other candidate genes for KS including NELF, FGF8, PKR2, and PK2 (23). Failure of gonadotrophin-induced testosterone production results in testicular maldescent. Partial pubertal development may be present in patients with partial defects, making early diagnosis difficult.
Contemporary genetics-based diagnostics of male infertility
Published in Expert Review of Molecular Diagnostics, 2019
Alberto Ferlin, Savina Dipresa, Andrea Delbarba, Filippo Maffezzoni, Teresa Porcelli, Carlo Cappelli, Carlo Foresta
Kallmann syndrome has a frequency of 1:10.000 and is characterized by hypogonadotropic hypogonadism (HH) (low serum level of testosterone, LH and FSH) and anosmia or hyposmia [68,69]. Beyond HH and midline defects such as cleft palate, other clinical features associated with Kallmann syndrome include tall stature, cryptorchidism, unilateral renal agenesis, and neurogenic deafness [68,69]. The most frequent genetic alteration responsible for this syndrome is a mutation in the X-linked gene KAL1 (14% of familial cases and 11% of sporadic cases), encoding the protein anosmin-1, which is a cell adhesion protein of the extracellular matrix. During embryogenesis, anosmin-1 is required for the organized migration of both olfactory axons and GnRH neurons from the olfactory placode through the cribriform plate and into the preoptic area of the hypothalamus. As such, defects result in anosmia and GnRH deficiency. GnRH deficiency results in subsequent lack of pulsatile LH that is required for normal gonadal function. Recent advance in this field, however, identified many other genes involved in HH mapping on chromosomes other than X chromosome (see below).
Site-specific protein biomarkers in gastric cancer: a comprehensive review of novel biomarkers and clinical applications
Published in Expert Review of Molecular Diagnostics, 2023
Takahiro Shinozuka, Mitsuro Kanda, Yasuhiro Kodera
In a single institutional retrospective study, we identified anosmin 1 (ANOS1) as a potential serum diagnostic marker for GC [63]. We thus conducted an international, multicenter, prospective study including 301 GC patients and 66 healthy controls to investigate the significance of ANOS1 as a diagnostic biomarker [51]. The AUC value for ANOS1 in distinguishing GC patients from healthy controls was 0.7058, with a sensitivity and specificity of 0.36 and 0.86, respectively. Furthermore, the AUC value of ANOS1 that discriminated patients with stage I GC from healthy controls was 0.7131. Serum ANOS1 levels were significantly increased in patients with stage I GC compared with healthy controls (P < 0.0001).
Molecular diagnostics of disorders of sexual development: an Indian survey and systems biology perspective
Published in Systems Biology in Reproductive Medicine, 2019
MR Nagaraja, Satya Prakash Gubbala, C. R. Wilma Delphine Silvia, Ramars Amanchy
KAL1 (mutations cause hypogonadotropic hypogonadism) encoded Anosmin-1 associates with most of the fibroblast growth factors and promote Leydig cell development (Liu et al. 2014) and ovarian follicle development (Wang et al. 2014). HDAC2 has been shown to regulate transcriptional events during oocyte development (Ma et al. 2012). Also, ACVR1 missense (c.772A>G; p.R258G) mutation shown to be involved in gonadal dysgenesis with sex reversal (Kaplan et al. 2015) could be a potential gene and can be used in screening efforts of DSD.