Kallmann Syndrome: Mutations in the Genes Encoding Prokineticin-2 and Prokineticin Receptor-2

Kallmann syndrome combines anosmia, related to defective olfactory bulb morphogenesis, and hypogonadism due to gonadotropin-releasing hormone deficiency. Loss-of-function mutations in KAL1 and FGFR1 underlie the X chromosome-linked form and an autosomal dominant form of the disease, respectively. Mutations in these genes, however, only account for approximately 20% of all Kallmann syndrome cases. In a cohort of 192 patients we took a candidate gene strategy and identified ten and four different point mutations in the genes encoding the G protein-coupled prokineticin receptor-2 (PROKR2) and one of its ligands, prokineticin-2 (PROK2), respectively. The mutations in PROK2 were detected in the heterozygous state, whereas PROKR2 mutations were found in the heterozygous, homozygous, or compound heterozygous state. In addition, one of the patients heterozygous for a PROKR2 mutation was also carrying a missense mutation in KAL1, thus indicating a possible digenic inheritance of the disease in this individual. These findings reveal that insufficient prokineticin-signaling through PROKR2 leads to abnormal development of the olfactory system and reproductive axis in man. They also shed new light on the complex genetic transmission of Kallmann syndrome

Complete exon sequencing of all known Usher syndrome genes greatly improves molecular diagnosis

<p>Abstract</p> <p>Background</p> <p>Usher syndrome (USH) combines sensorineural deafness with blindness. It is inherited in an autosomal recessive mode. Early diagnosis is critical for adapted educational and patient management choices, and for genetic counseling. To date, nine causative genes have been identified for the three clinical subtypes (USH1, USH2 and USH3). Current diagnostic strategies make use of a genotyping microarray that is based on the previously reported mutations. The purpose of this study was to design a more accurate molecular diagnosis tool.</p> <p>Methods</p> <p>We sequenced the 366 coding exons and flanking regions of the nine known USH genes, in 54 USH patients (27 USH1, 21 USH2 and 6 USH3).</p> <p>Results</p> <p>Biallelic mutations were detected in 39 patients (72%) and monoallelic mutations in an additional 10 patients (18.5%). In addition to biallelic mutations in one of the USH genes, presumably pathogenic mutations in another USH gene were detected in seven patients (13%), and another patient carried monoallelic mutations in three different USH genes. Notably, none of the USH3 patients carried detectable mutations in the only known USH3 gene, whereas they all carried mutations in USH2 genes. Most importantly, the currently used microarray would have detected only 30 of the 81 different mutations that we found, of which 39 (48%) were novel.</p> <p>Conclusions</p> <p>Based on these results, complete exon sequencing of the currently known USH genes stands as a definite improvement for molecular diagnosis of this disease, which is of utmost importance in the perspective of gene therapy.</p

Normal and abnormal interchanges between the human X and Y chromosomes.

International audienceA single obligatory recombination event takes place at male meiosis in the tips of the X- and Y-chromosome short arms (i.e. the pseudoautosomal region). The crossover point is at variable locations and thus allows recombination mapping of the pseudoautosomal loci along a gradient of sex linkage. Recombination at male meiosis in the terminal regions of the short arms of the X and Y chromosomes is 10- to 20-fold higher than between the same regions of the X chromosomes during female meiosis. The human pseudoautosomal region is rich in highly polymorphic loci associated with minisatellites. However, these minisatellites are unrelated to those resembling the bacterial Chi sequence and which possibly represent recombination hotspots. The high recombination activity of the pseudoautosomal region at male meiosis sometimes results in unequal crossover which can generate various sex-reversal syndromes

Les surdités héréditaires: génétique moléculaire

Durant les dix dernières années, des progrès substantiels ont été réalisés dans la compréhension, en termes moléculaires, des surdités héréditaires congénitales ou d’apparition précoce. Cet article porte essentiellement sur les surdités isolées (i.e. non syndromiques), pour lesquelles le nombre de gènes responsables identifiés (36 à ce jour) s’accroît rapidement. En revanche, des difficultés inhérentes à l’analyse de liaison génétique, auxquelles s’ajoute l’implication de facteurs environnementaux, ont jusqu’à présent empêché la caractérisation des principaux gènes responsables de, ou prédisposant à, l’apparition d’une surdité tardive.This article outlines recent advances in explaining hereditary deafness in molecular terms, focusing on isolated (i.e. nonsyndromic) hearing loss. The number of genes identified (36 to date) is growing rapidly. However, difficulties inherent in genetic linkage analysis, coupled with the possible involvement of environmental causes, have so far prevented the characterization of the main genes causative or predisposing to the late-onset forms of deafness

Isolation of sequences from Xp22.3 and deletion mapping using sex chromosome rearrangements from human X-Y interchange sex reversals

International audienceA repeated DNA element (STIR) interspersed in Xp22.3 and on the Y chromosome has been used as a tag to isolate seven single-copy probes from the human sex chromosomes. The seven probes detect X-specific loci located in Xp22.3. Using a panel of X-chromosomal deletions from X-Y interchange sex reversals (XX males and XY females), these X-specific loci and some additional ones were mapped to four contiguous intervals of Xp22.3, proximal to the pseudoautosomal region and distal to STS. The construction of this deletion map of the terminal part of the human X chromosome can serve as a starting point for a long-range physical map of Xp22.3 and for a more accurate mapping of genetic diseases located in Xp22.3

An abnormal terminal X-Y interchange accounts for most but not all cases of human XX maleness

To determine if human XX maleness results from an abnormal chromosomal X-Y interchange, we studied the inheritance of the paternal pseudoautosomal region in nine patients. Those six patients in whom Y-specific DNA was found (Y(+)) inherited the entire pseudoautosomal region from the paternal Y chromosome and lost that of the paternal X chromosome. Moreover, in three Y(+) cases, we observed the deletion of a paternal Xp locus tightly linked to the pseudoautosomal region. These results definitively show that an abnormal and terminal X-Y interchange during paternal meiosis causes Y(+)XX maleness. In contrast, no abnormal X-Y interchange was observed in any of the three Y(-) cases analyzed, suggesting that maleness can occur in the absence of any Y-specific DNA. © 1987

Approche moléculaire de la pathogénie d'un deficit héréditaire de l'olfaction : Le syndrome de Kallmann de Morsier lie au chromosome X

International audienceLe syndrome de Kallmann de Morsier associe une anosmie (deficit de l'olfaction) a un hypogonadisme. L'hypogonadisme est dû a un deficit en GnRH, hormone hypothalamique qui contrôle via l'hypophyse le développement pubertaire des gonades. L'anosmie s'accompagne de l'aplasie des bulbes olfactifs. Nous avons isolé en 1991 le gene KAL, responsable de la forme liée au chromosome X de ce syndrome. L'analyse des sites d'expression du gene et de la localisation de la protéine dans le système nerveux central chez l'embryon de poulet, suggère que le deficit de l'olfaction qui caractérise la maladie serait la consequence d'une anomalie primitive du développement des bulbes olfactifs

The candidate gene for the X-linked Kallmann syndrome encodes a protein related to adhesion molecules

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Whole exome sequencing identifies new causative mutations in Tunisian families with non-syndromic deafness.

Identification of the causative mutations in patients affected by autosomal recessive non syndromic deafness (DFNB forms), is demanding due to genetic heterogeneity. After the exclusion of GJB2 mutations and other mutations previously reported in Tunisian deaf patients, we performed whole exome sequencing in patients affected with severe to profound deafness, from four unrelated consanguineous Tunisian families. Four biallelic non previously reported mutations were identified in three different genes: a nonsense mutation, c.208C>T (p.R70X), in LRTOMT, a missense mutation, c.5417T>C (p.L1806P), in MYO15A and two splice site mutations, c.7395+3G>A, and c.2260+2T>A, in MYO15A and TMC1 respectively. We thereby provide evidence that whole exome sequencing is a powerful, cost-effective screening tool to identify mutations causing recessive deafness in consanguineous families