PubMed Health⌕ Search

Biomedical subjects

Jean-Pierre Hardelin

Publications and source records attributed to Jean-Pierre Hardelin.

16 recordsLinked to original sources
PubMed2007

Novel FGFR1 sequence variants in Kallmann syndrome, and genetic evidence that the FGFR1c isoform is required in olfactory bulb and palate morphogenesis.

In a new cohort of 141 unrelated patients affected by Kallmann syndrome we identified FGFR1 sequence variants in 17 patients, all in the heterozygous state. The fifteen novel variants consist of 10 missense (p.N77K, p.C101F, p.R250W, p.G270D, p.P283R, p.S332C, p.H621R, p.S685F, p.I693F, p.R822C), two nonsense (p.E324X, p.R661X), a frameshift (p.S439fs), and two splice site (c.1081G>C and c.1977+1G>A) changes. However, the p.N77K and p.R822C changes were also found in two and one out of 150 healthy control individuals, respectively, and therefore, their pathogenic effect is questionable. Notably, three alterations (p.E324X, p.S332C, c.1081G>C) are located in the alternative exon 8B that codes for the FGFR1c isoform, thus indicating that this isoform plays a crucial role in the development of the olfactory system in man. Moreover, the presence of cleft palate in a patient carrying the p.E324X change shows that FGFR1c is important for palate morphogenesis too.

DNA Mutational Analysis↗
PubMed2006

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.

Chromosome Segregation↗
PubMed2005

PHR1, an integral membrane protein of the inner ear sensory cells, directly interacts with myosin 1c and myosin VIIa.

By using the yeast two-hybrid technique, we identified a candidate protein ligand of the myosin 1c tail, PHR1, and found that this protein can also bind to the myosin VIIa tail. PHR1 is an integral membrane protein that contains a pleckstrin homology (PH) domain. Myosin 1c and myosin VIIa are two unconventional myosins present in the inner ear sensory cells. We showed that PHR1 immunoprecipitates with either myosin tail by using protein extracts from cotransfected HEK293 cells. In vitro binding assays confirmed that PHR1 directly interacts with these two myosins. In both cases the binding involves the PH domain. In vitro interactions between PHR1 and the myosin tails were not affected by the presence or absence of Ca2+ and calmodulin. Finally, we found that PHR1 is able to dimerise. As PHR1 is expressed in the vestibular and cochlear sensory cells, its direct interactions with the myosin 1c and VIIa tails are likely to play a role in anchoring the actin cytoskeleton to the plasma membrane of these cells. Moreover, as both myosins have been implicated in the mechanotransduction slow adaptation process that takes place in the hair bundles, we propose that PHR1 is also involved in this process.

Animals↗
PubMed2005

Kallmann syndrome: 14 novel mutations in KAL1 and FGFR1 (KAL2).

Kallmann syndrome (KAL) combines hypogonadotropic hypogonadism and anosmia. Hypogonadism is due to Gonadotropin Releasing Hormone (GnRH) deficiency and anosmia is related to hypoplasia of the olfactory bulbs. Occasional symptoms include renal agenesis, bimanual synkinesia, cleft lip palate, dental agenesis. KAL is genetically heterogeneous and two genes have so far been identified, namely KAL1 (Xp22.3) and FGFR1/KAL2 (8p12), which underlie the X chromosome-linked form and an autosomal dominant form of the disease, respectively. We studied a cohort of 98 unrelated Caucasian KAL patients. We identified KAL1 mutations in 14 patients, of which 7 (c.3G>A (p.M1?), g.IVS1+1G>T, c.570_571insA (p.R191fsX14), c.784G>C (p.R262P), c.958G>T (p.E320X), c.1651_1654delinsAGCT (p.P551_E552delinsSX), c.1711T>A (p.W571R)) have not been previously reported. In addition, we found FGFR1 mutations in 7 patients, namely c.303G>A (p.V102I), C.385A>C (p.D129A), c.810G>A (p.V273M), c.1093_1094delAG (p.R365fsX41), c.1561G>A (p.A520T), c.1836_1837insT (p.Y613fsX42), c.2190C>G (p.Y730X), all of which were novel mutations. In this study, unilateral renal agenesis and bimanual synkinesia were exclusively found associated with KAL1mutations, cleft palate and dental agenesia with FGFR1mutations.

DNA Mutational Analysis↗
PubMed2005

Coexistence of Kallmann syndrome and complete androgen insensitivity in the same patient.

Kallmann syndrome (KS) is a developmental disease that combines hypogonadotropic hypogonadism and anosmia/hyposmia. Other congenital abnormalities may also coexist. This present report describes two sisters, aged 13 and 12 years, born from Lebanese consanguineous parents. The two sisters have complete androgen insensitivity (normal female appearance and an XY karyotype) due to a novel mutation, a C-to-G transversion in intron 2 of the androgen receptor gene, resulting in an aberrant splicing leading to an insertion of 66 nucleotides in the mRNA. In addition, the older sister has KS, together with synkinesia and multiple skeletal abnormalities, mainly kyphosis, vertebral abnormalities, and short right hand and feet. Her testosterone, FSH and LH levels were very low compared with her younger sister. No mutation in the KAL1 and FGFR1/KAL2 genes were found. This unique report raises the possibility of an autosomal recessive or X-linked form of KS with new phenotypic expression.

Adolescent↗
PubMed2004

Myosin XVa and whirlin, two deafness gene products required for hair bundle growth, are located at the stereocilia tips and interact directly.

Defects in myosin XVa and the PDZ domain-containing protein, whirlin, underlie deafness in humans and mice. Hair bundles of mutant mice defective for either protein have abnormally short stereocilia. Here, we show that whirlin, like myosin XVa, is present at the very tip of each stereocilium in the developing and mature hair bundles of the cochlear and vestibular system. We found that myosin XVa SH3-MyTH4 region binds to the short isoform of whirlin (PR-PDZ3) that can rescue the stereocilia growth defect in whirlin defective mice. Moreover, the C-terminal MyTH4-FERM region of myosin XVa binds to the PDZ1 and PDZ2 domains of the long whirlin isoform. We conclude that a direct myosin XVa-whirlin interaction at the stereocilia tip is likely to control the elongation of stereocilia. Whirlin, unlike myosin XVa, is also transiently localized in the basal region of developing stereocilia in rat vestibular and cochlear hair cells until P4 and P12, respectively. Notably, whirlin also interacts with myosin VIIa that is present along the entire length of the stereocilia. Finally, we show that the transmembrane netrin-G1 ligand (NGL-1) binds to the PDZ1 and PDZ2 domains of whirlin and has an extracellular region that homophilically self-interacts in a Ca2+-dependent manner. The interaction between whirlin and NGL-1 might be involved in the stabilization of interstereociliar links.

Actins↗
PubMed2004

Kallmann syndrome: fibroblast growth factor signaling insufficiency?

Kallmann syndrome (KAL) is a developmental disease that combines hypogonadotropic hypogonadism and anosmia. Anosmia is related to the absence or hypoplasia of the olfactory bulbs. Hypogonadism is due to GnRH deficiency and is likely to result from the failed embryonic migration of GnRH-synthesizing neurons. These cells normally migrate from the olfactory epithelium to the forebrain along the olfactory nerve pathway. KAL is phenotypically and genetically heterogeneous. The gene responsible for the X-chromosome linked form of the disease (KAL1) has been identified in 1991. KAL1 encodes anosmin-1, an approximately 95-kDa glycoprotein of unknown function which is present locally in various extracellular matrices during the period of organogenesis. The recent finding that FGFR1 mutations are involved in an autosomal dominant form of Kallmann syndrome (KAL2), combined with the analysis of mutant mouse embryos that no longer express Fgfr1 in the telencephalon, suggests that the disease results from a deficiency in FGF signaling at the earliest stage of olfactory bulb morphogenesis. We propose that the role of anosmin-1 is to enhance FGF signaling and suggest that the gender difference in anosmin-1 dose (because KAL1 partially escapes X-inactivation) explains the higher prevalence of the disease in males.

Extracellular Matrix Proteins↗
PubMed2004

[Hereditary deafness: molecular genetics].

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.

Age of Onset↗
PubMed2003

Loss-of-function mutations in FGFR1 cause autosomal dominant Kallmann syndrome.

We took advantage of overlapping interstitial deletions at chromosome 8p11-p12 in two individuals with contiguous gene syndromes and defined an interval of roughly 540 kb associated with a dominant form of Kallmann syndrome, KAL2. We establish here that loss-of-function mutations in FGFR1 underlie KAL2 whereas a gain-of-function mutation in FGFR1 has been shown to cause a form of craniosynostosis. Moreover, we suggest that the KAL1 gene product, the extracellular matrix protein anosmin-1, is involved in FGF signaling and propose that the gender difference in anosmin-1 dosage (because KAL1 partially escapes X inactivation) explains the higher prevalence of the disease in males.

Cell Adhesion Molecules↗
PubMed2003

Anosmin-1 immunoreactivity during embryogenesis in a primitive eutherian mammal.

Kallmann syndrome is hypogonadotropic hypogonadism coupled with anosmia. A morphological study found that the endocrine disorder in X-linked Kallmann syndrome is due to failed migration of gonadotropin releasing-hormone (GnRH) neurons from the olfactory placode to the brain during development. Anosmia results from agenesis of the olfactory bulbs and tracts. The gene responsible for the X-linked form of Kallmann syndrome, KAL-1, has been characterized. The orthologues of KAL-1 have been isolated in the chick and the zebrafish, but still await identification in rodents. In the present study, we used polyclonal and monoclonal antibodies to the human KAL-1 encoded protein, anosmin-1, in a primitive mammal, the Asian musk shrew. Musk shrews are insectivores and are therefore evolutionarily closer to primates than rodents. By immunoblot analysis of musk shrew tissues, a band of the expected apparent molecular mass (95 kDa) was detected in several structures of the central nervous system, but not in liver or muscle, which is consistent with the gene expression pattern previously reported in the chick. By immunohistochemical analysis, anosmin-1 was detected in the developing olfactory epithelium, the olfactory, vomeronasal and terminalis nerves, the olfactory bulbs, the cerebellum and the cerebral cortex and in several other regions of the brain, during musk shrew embryogenesis. Furthermore, migrating gonadotropin releasing-hormone (GnRH)-immunoreactive neurons were seen in close association with anosmin-1-immunoreactive fibers. Assuming that the protein is present at the surface of these fibers, we suggest a possible direct role of anosmin-1 in the migration of GnRH neurons in this species.

Animals↗
PubMed2003

Connexin30 (Gjb6)-deficiency causes severe hearing impairment and lack of endocochlear potential.

The gap junction protein connexin30 (Cx30) is expressed in a variety of tissues that include epithelial and mesenchymal structures of the inner ear. We generated Cx30 (Gjb6) deficient mice by deletion of the Cx30 coding region. Homozygous mutants (Cx30((-/-))) were born at the expected Mendelian frequency, developed normally and were fertile. However, they exhibit a severe constitutive hearing impairment. From the age of hearing onset, these mice lack the electrical potential difference between the endolymphatic and perilymphatic compartments of the cochlea, i.e. the endocochlear potential, which plays a key role in the high sensitivity of the mammalian auditory organ. In addition, after postnatal day 18, the cochlear sensory epithelium starts to degenerate by cell apoptosis. This degeneration process is likely to account for the concomitant decrease of the endolymphatic potassium concentration and the aggravation of the hearing loss in adult Cx30((-/-)) mice. The Cx30 ((-/-)) phenotype thus reveals the critical role of Cx30 both in generating the endocochlear potential and for survival of the auditory hair cells after the onset of hearing. The Cx30 deficient mice may represent a valuable model to study the mechanism of the hearing loss in human patients carrying a homozygous deletion of the CX30 gene (del Castillo et al., 2002, New Engl. J. Med., 346, 243-249).

Alleles↗
PubMed2003

X chromosome-linked Kallmann syndrome: clinical heterogeneity in three siblings carrying an intragenic deletion of the KAL-1 gene.

Kallmann syndrome (KS) is characterized by the association of hypogonadotropic hypogonadism and anosmia. The gene underlying the X chromosome-linked form of the disease, KAL-1, consists of 14 coding exons. It encodes a glycoprotein, anosmin-1, which is involved in the embryonic migration of GnRH-synthesizing neurons and the differentiation of the olfactory bulbs. We describe herein the clinical heterogeneity in three affected brothers who carry a large deletion (exons 3-13) in KAL-1. All three had a history of hypogonadotropic hypogonadism with delayed puberty. Although brain magnetic resonance imaging showed hypoplastic olfactory bulbs in the three siblings, variable degrees of anosmia/hyposmia were shown by olfactometry. In addition, these brothers had different phenotypic anomalies, i.e. unilateral renal aplasia (siblings B and C), high-arched palate (sibling A), brachymetacarpia (sibling A), mirror movements (siblings A and B), and abnormal eye movements (sibling C). Last but not least, sibling A suffered from a severe congenital hearing impairment, a feature that had been reported in KS but had not yet been ascribed unambiguously to the X-linked form of the disease. The variable phenotype, both qualitatively and quantitatively, in this family further emphasizes the role of putative modifier genes, and/or epigenetic factors, in the expressivity of the X-linked KS.

Adolescent↗
PubMed2002

A subtracted cDNA library from the zebrafish (Danio rerio) embryonic inner ear.

A database was built that consists of 4694 sequence contigs of approximately 18,000 reads of cDNAs isolated from the microdissected otocysts of zebrafish embryos at 20-30 hour postfertilization, following subtraction with a pool of liver cDNAs from adult fish. These sequences were compared with those of public databanks. Significant similarity were recorded and organized in a relational database at http://www.genoscope.cns.fr/zie. A first group of 2067 sequences correspond to 1428 known zebrafish genes or ESTs present in the Danio rerio section of UniGene. A second group of 302 sequences encode putative proteins that showed significant similarity (50%-100%) with 302 nonzebrafish proteins in the nr databank, a public databank containing an exhaustive nonredundant collection of protein sequences from different species (ftp://ftp.ncbi.nlm.nih.gov/blast/db/nr). The remaining 2325 (49.5%) sequence contigs or singletons showed no significant similarity with sequences available in public databanks. Several genes known to be expressed in the developing inner ear were represented in the present database, in particular genes involved in hair cell differentiation or innervation The occurrence of these genes validates the outcome of this study as the first collection of ESTs preferentially expressed in the zebrafish inner ear during the period of hair cell differentiation and neuroblast delamination from the otic vesicle epithelium. Novel zebrafish genes also involved in these processes are thus likely to be represented among the sequences obtained herein, for which no homology was found in the D. rerio section of UniGene. [The sequence data from this study have been submitted to EMBL under accession nos. AL714032-AL731531].

Animals↗
PubMedDate not supplied

[Kallmann De Morsier syndrome: FGF-signaling insufficiency?].

Kallmann syndrome (KAL) associates hypogonadotropic hypogonadism and anosmia, i.e. a deficiency of the sense of smell. Anosmia is related to the absence or the hypoplasia of the olfactory bulbs. Hypogonadism is due to GnRH deficiency, and is likely to result from the failed embryonic migration of GnRH-synthesizing neurons. These cells normally migrate from the olfactory epithelium to the forebrain along the olfactory nerve pathway. Kallmann syndrome is genetically heterogeneous. The gene responsible for the X-chromosome linked form of the disease, KAL-1, has been identified in 1991. KAL1 encodes a ~95 kDa glycoprotein of unknown function, which is present locally in various extracellular matrices during the period of organogenesis. The recent finding that FGFR1 mutations are involved in an autosomal dominant form of Kallmann syndrome (KAL-2), combined to the analysis of mutant mouse embryos that no longer express Fgfr1 in the telencephalon, suggests that the disease results from a deficiency in FGF-signaling at the earliest stage of olfactory bulb morphogenesis. We propose that the role of the KAL1 gene product, the extracellular matrix protein anosmin-1, is to enhance FGF-signaling, and suggest that the gender difference in anosmin-1 dosage (because KAL1 partially escapes X-inactivation) explains the higher prevalence of the disease in males.

Biomedical Research↗
PubMedDate not supplied

[Usher syndrome type I and the differentiation of inner ear sensory cells' hair bundles].

Defects in myosin VIIa, the PDZ-domain-containing protein harmonin, cadherin 23, protocadherin 15, and the putative scaffolding protein sans, underlie five genetic forms of Usher syndrome type I (USH1), the most frequent cause of hereditary deafness-blindness in humans. Mice mutants defective for any of these proteins have a severe hearing impairment and display similar inner ear phenotypes characterized by the abnormal spreading of the sensory cells' stereocilia. These are highly specialized mechanoreceptive organelles derived from microvilli, that normally form a well-structured hair bundle at the apex of inner ear sensory cells. All the USH1 proteins, except sans, have been detected in the growing stereocilia. Moreover, biochemical studies have started to unravel the multiple direct molecular interactions between USH1 proteins. In particular, harmonin can bind to the other four USH1 proteins and to F-actin. Finally, cell biology studies have provided the first insights into the functions of these proteins, and revealed that cadherin 23, and probably protocadherin 15 also, are associated with transient lateral links that interconnect growing stereocilia. These connectors play a critical role in the differentiating hair bundle.

Animals↗