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      A Tunisian Patient with Two Rare Syndromes: Triple A Syndrome and Congenital Hypogonadotropic Hypogonadism

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          Background/Aims: The coexistence of triple A syndrome (AAAS) and congenital hypogonadotropic hypogonadism (CHH) has so far not been reported in the literature. This study aimed to characterize at the clinical and genetic level one patient presenting an association of AAAS and CHH in order to identify causal mutations. Methods: Clinical and endocrinal investigations were performed and followed by mutational screening of candidate genes. Results: At the age of 18, the patient presented sexual infantilism, a micropenis and gynecomastia. No mutation was revealed in GnRHR, TACR3/ TAC3, PROK2/ PROKR2 and PROP1 genes, except a homozygous intronic variation (c.244 + 128C>T; dbSNP: rs350129) in the KISS1R gene, which is likely nondeleterious. A homozygous splice-donor site mutation (IVS14 + 1G>A) was found in the AAAS gene. This mutation, responsible for AAAS, is a founder mutation in North Africa. Conclusion: This is the first report on a Tunisian patient with the coexistence of AAAS and CHH. The diagnosis of CHH should be taken in consideration in patients with Allgrove syndrome and who carry the IVS14 + 1G>A mutation as this might challenge appropriate genetic counseling.

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          Most cited references 32

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          Oligogenic basis of isolated gonadotropin-releasing hormone deficiency.

          Between the genetic extremes of rare monogenic and common polygenic diseases lie diverse oligogenic disorders involving mutations in more than one locus in each affected individual. Elucidating the principles of oligogenic inheritance and mechanisms of genetic interactions could help unravel the newly appreciated role of rare sequence variants in polygenic disorders. With few exceptions, however, the precise genetic architecture of oligogenic diseases remains unknown. Isolated gonadotropin-releasing hormone (GnRH) deficiency caused by defective secretion or action of hypothalamic GnRH is a rare genetic disease that manifests as sexual immaturity and infertility. Recent reports of patients who harbor pathogenic rare variants in more than one gene have challenged the long-held view that the disorder is strictly monogenic, yet the frequency and extent of oligogenicity in isolated GnRH deficiency have not been investigated. By systematically defining genetic variants in large cohorts of well-phenotyped patients (n = 397), family members, and unaffected subjects (n = 179) for the majority of known disease genes, this study suggests a significant role of oligogenicity in this disease. Remarkably, oligogenicity in isolated GnRH deficiency was as frequent as homozygosity/compound heterozygosity at a single locus (2.5%). Among the 22% of patients with detectable rare protein-altering variants, the likelihood of oligogenicity was 11.3%. No oligogenicity was detected among controls (P < 0.05), even though deleterious variants were present. Viewing isolated GnRH deficiency as an oligogenic condition has implications for understanding the pathogenesis of its reproductive and nonreproductive phenotypes; deciphering the etiology of common GnRH-related disorders; and modeling the genetic architecture of other oligogenic and multifactorial diseases.
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            Kallmann Syndrome: Mutations in the Genes Encoding Prokineticin-2 and Prokineticin Receptor-2

            Introduction Kallmann syndrome (KS) combines hypogonadotropic hypogonadism and anosmia or hyposmia, i.e., a deficiency of the sense of smell [1]. Anosmia/hyposmia is related to the absence or hypoplasia of the olfactory bulbs and tracts [2]. Hypogonadism is due to deficiency in gonadotropin-releasing hormone [3] and probably results from a failure of embryonic migration of gonadotropin-releasing hormone-synthesizing neurons [4]. These cells normally migrate from the olfactory epithelium to the forebrain along the olfactory nerve pathway [5]. In some KS patients other developmental anomalies can be present, which include renal agenesis, cleft lip and/or palate, selective tooth agenesis, and bimanual synkinesis [6]. This is a genetically heterogeneous disease, which affects 1:8000 males and approximately five times less females. Two different genes have so far been identified. Loss-of-function mutations in KAL1 (NCBI GeneID: 3730) [7–9] and FGFR1 (NCBI GeneID: 2260) [10] account for the X-chromosome linked form and an autosomal dominant form of the disease, respectively. KAL1 encodes anosmin-1, a locally restricted glycoprotein of embryonic extracellular matrices [11], which is likely to be involved in fibroblast growth factor-signaling [6,12]. Nearly 80% of the KS patients, however, do not carry a mutation in either of these genes [6]. Because the common infertility in affected individuals and, most importantly, the incomplete penetrance of the disease impede linkage analysis, the positional cloning strategies that have been taken to find causative genes were based on the analysis of rare KS individuals who carry chromosomal rearrangements detectable by cytogenetics techniques [7,8,10]. Here, we used a direct candidate gene approach and identified two novel genes underlying the disease. Results/Discussion We first considered GPR73L1/PROKR2 (NCBI GeneID: 128674), encoding the prokineticin receptor-2 (PROKR2) [13–15], a most relevant candidate because olfactory bulbs do not develop normally in mutant mice lacking this G protein-coupled transmembrane receptor, and these mice also have a severe atrophia of the reproductive system related to the absence of gonadotropin-releasing hormone-synthesizing neurons in the hypothalamus [16]. We thus sequenced the two coding exons of PROKR2 and flanking splice sites in 192 unrelated individuals (144 males and 48 females) affected by KS, including 38 familial cases. Ten different mutations (one frameshift and nine missense mutations) were detected in 14 patients (four familial and ten apparently sporadic cases) in the heterozygous (ten cases), homozygous (two cases), or compound heterozygous (two cases) state (Figure S1, Table 1, and Figure 1). Conservation of the mutated amino acid residues in bovine, murine, and rat orthologous sequences (Figure S2) argues in favor of a deleterious effect for all the missense mutations. However, two of these mutations, p.R268C and p.V331M, as well as a mutation (c.253C>T, p.R85C) affecting the same residue as the p.R85H mutation found in two KS cases and another missense mutation (c.1004C>G, p.T335M) not found in the cohort of KS patients, were detected, once each, in 500 alleles from ethnically matched (Caucasian) control individuals. No other nonsynonymous variant was found in the controls. In the absence of functional testing, one cannot be sure that each missense mutation found in KS individuals is causative of the disease. Nevertheless, together with the KS-like phenotype of Prokr2 knockout mice, the fact that the overall proportion of PROKR2 alleles carrying nonsynonymous mutations is significantly higher in KS patients (18 out of 384 alleles) than in controls (four out of 500 alleles; chi-square value = 13.5, p A (p.R85H) and c.518T>G (p.L173R), were also found in the homozygous state in one patient each. (2.4 MB TIF) Click here for additional data file. Figure S2 Alignment of PROKR2 and PROK2 Amino Acid Sequences in Man, Cow, Mouse, and Rat (CLUSTALW) The missense mutations found in Kallmann syndrome patients are indicated by arrowheads. In the PROK2 sequence, the additional peptide encoded by exon 3 (alternative splicing) is underlined, and the N-terminal AVITGA motif that is critical for the bioactivity of the protein is highlighted in yellow. (91 KB PDF) Click here for additional data file. Figure S3 DNA Sequence Electrophoretograms from the Kallmann Syndrome Patient Carrying Missense Mutations in PROKR2 and KAL1, and Interspecies Comparison of the Amino Acid Sequence of KAL1 (Anosmin-1) around the Mutated Residue Control electrophoretograms are shown on the top. The mutations in PROKR2 and KAL1 are indicated by vertical arrows on the patient's electrophoretograms (bottom). Alignment of the KAL1 amino acid sequences from man, cow, chicken, zebrafish (kal1.1 and kal1.2), Caenorhabditis elegans, and Drosophila melanogaster shows the conservation of the mutated residue (Ser396) in vertebrates and invertebrates (either serine or threonine), whereas most of the surrounding residues are more variable. (943 KB TIF) Click here for additional data file.
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              Mutant WD-repeat protein in triple-A syndrome.

              Triple-A syndrome (MIM 231550; also known as Allgrove syndrome) is an autosomal recessive disorder characterized by adrenocorticotropin hormone (ACTH)-resistant adrenal insufficiency, achalasia of the oesophageal cardia and alacrima. Whereas several lines of evidence indicate that triple-A syndrome results from the abnormal development of the autonomic nervous system, late-onset progressive neurological symptoms (including cerebellar ataxia, peripheral neuropathy and mild dementia) suggest that the central nervous system may be involved in the disease as well. Using fine-mapping based on linkage disequilibrium in North African inbred families, we identified a short ancestral haplotype on chromosome 12q13 (<1 cM), sequenced a BAC contig encompassing the triple-A minimal region and identified a novel gene (AAAS) encoding a protein of 547 amino acids that is mutant in affected individuals. We found five homozygous truncating mutations in unrelated patients and ascribed the founder effect in North African families to a single splice-donor site mutation that occurred more than 2,400 years ago. The predicted product of AAAS, ALADIN (for alacrima-achalasia-adrenal insufficiency neurologic disorder), belongs to the WD-repeat family of regulatory proteins, indicating a new disease mechanism involved in triple-A syndrome. The expression of the gene in both neuroendocrine and cerebral structures points to a role in the normal development of the peripheral and central nervous systems.

                Author and article information

                Horm Res Paediatr
                Hormone Research in Paediatrics
                S. Karger AG
                November 2014
                18 September 2014
                : 82
                : 5
                : 338-343
                aLR11IPT05, Laboratoire de Génomique Biomédicale et Oncogénétique, Institut Pasteur de Tunis, Université de Tunis El Manar, bService d'Endocrinologie, Hôpital Charles-Nicolle, and cService d'Endocrinologie, Institut de Nutrition, Tunis, Tunisia
                Author notes
                *Youssef Lakhoua, Département d'Endocrinologie, Hôpital Charles-Nicolle, Boulevard 9 Avril 1938, Tunis 1006 (Tunisia), E-Mail laksoso@yahoo.fr
                365888 Horm Res Paediatr 2014;82:338-343
                © 2014 S. Karger AG, Basel

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                Figures: 2, Tables: 2, Pages: 6
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