Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nerve cells that express luteinizing hormone-releasing hormone (LHRH), essential for reproductive functions, originate in the epithelium of the medial olfactory placode. While the peripheral origin of this physiologically important brain peptide is surprising, associations between olfactory and reproductive systems are well documented in behavioral studies of pheromones and in clinical studies of disorders including hypogonadotropic hypogonadism with anosmia or olfactory-genital dysplasia. Mechanisms underlying this migration include a close association with neural cell adhesion molecules (NCAM), but are likely also to involve other physical and chemical factors.
J Steroid Biochem Mol Biol 1991 Oct
PMID:Migration of LHRH-immunoreactive neurons from the olfactory placode rationalizes olfacto-hormonal relationships. 189 87

In mammals, primer pheromones are considered as the most important signals involved in socio-sexual stimulation of the reproductive processes. In the domestic sheep, male-female interactions induce changes in the pulsatile rhythm of the LH secretion in both sexes which influences reproductive endocrinology. In the female, the odor of the ram's fleece induces LH secretion and ovulation. The acid sub fraction of the methylene chloride extract under C16 and diols appear to contain the active components. An interspecific action has been observed, as male goat's hair extract is similarly active. In the male, although the receptive female is the most effective to stimulate LH release, no pheromonal action has been demonstrated. In the female, lesions of the vomeronasal system do not eliminate the endocrine response to pheromonal stimulation. Furthermore, in both sexes, anosmia does not impair the response to direct interaction with the sexual partner. In domestic sheep, the existence of primer pheromones has been demonstrated, but other sensory cues could replace olfaction during socio-sexual interactions interfering with the control of reproductive endocrinology.
J Steroid Biochem Mol Biol 1991 Oct
PMID:Sexual pheromones in the domestic sheep: importance and limits in the regulation of reproductive physiology. 189 93

Kallmann syndrome inherited hypogonadotropic hypogonadism with anosmia, is associated with an X-chromosome deletion at Xp 22.3. In a Kallmann fetus, we have found an absence of luteinizing hormone-releasing hormone (LHRH)-expressing cells in the brain despite dense clusters of LHRH cells and fibers in the nose. LHRH-containing cells and neurites end in a tangle beneath the forebrain, within the dural layers of the meninges, on the dorsal surface of the cribriform plate of the ethmoid bone. Normal fetal brains, matched for age and sex, had LHRH cells and fibers, as expected, in the hypothalamus and preoptic area. Since LHRH-expressing cells recently were discovered to migrate from the olfactory placode into the brain, it appears that the hypogonadotropism of the Kallmann syndrome can be accounted for by a failure of LHRH cells to migrate into the brain.
Brain Res Mol Brain Res 1989 Dec
PMID:Luteinizing hormone-releasing hormone (LHRH)-expressing cells do not migrate normally in an inherited hypogonadal (Kallmann) syndrome. 268 10

Kallmann's syndrome (KS) is characterised by the association of anosmia and isolated hypogonadotrophic hypogonadism (IHH). Mutations of the KAL gene which is located at Xp22.3 cause X-linked KS (XKS). In this study we used the reverse transcriptase polymerase chain reaction and in situ hybridisation to examine the developmental expression of KAL in the first trimester of pregnancy, the earliest stage of human gestation examined thus far. At 45 days after fertilisation KAL mRNA was detected in the spinal cord, the mesonephros and metanephros but not in the brain. Later in gestation, at 11 weeks, the gene was expressed in the developing olfactory bulb, retina and kidney. This expression pattern correlates with the clinical findings in XKS since olfactory bulb dysgenesis with subsequent defective neural migration causes anosmia and IHH. Additionally, renal agenesis occurs in 40% of patients. Therefore this study provides strong evidence that KAL expression is required for the normal development of the olfactory bulb and kidney in the first trimester of human pregnancy.
Mol Cell Endocrinol 1995 Apr 28
PMID:KAL, a gene mutated in Kallmann's syndrome, is expressed in the first trimester of human development. 754 24

Kallmann syndrome represents the association of hypogonadotropic hypogonadism with anosmia. Three modes of transmission, X chromosome-linked, autosomal recessive and autosomal dominant, have been described. The KAL gene, responsible for the X-linked form of the disease, has been isolated and its intron-exon organization recently determined. We have searched for mutations of the KAL gene in 21 unrelated males affected by familial Kallmann syndrome. In these families, segregation of the disease was suggestive of the X-linked mode of transmission. In 2 families, large Xp22.3 deletions, both including the entire KAL gene, have been detected by Southern blot analysis. Here we report the sequence analysis of the entire coding region of the KAL gene in the 19 remaining patients. The approach consisted of sequencing each of the 14 coding exons and splice site junctions. Each exon was amplified by PCR on the genomic DNA, using oligonucleotides from the flanking intronic sequences as specific primers. Nine point mutations were identified at separate locations in four exons and one splice site, providing strong evidence for heterogeneity in mutations responsible for the X-linked Kallmann syndrome. In addition, the high frequency of unilateral renal aplasia in X-linked Kallmann patients (6 out of 11 males with identified alterations of the KAL gene) should be emphasized.
Hum Mol Genet 1993 Apr
PMID:Heterogeneity in the mutations responsible for X chromosome-linked Kallmann syndrome. 850 98

Kallmann syndrome is characterized by hypogonadotropic hypogonadism and anosmia and caused by a defect of migration and targeting of gonadotropin-releasing hormone-secreting neurons and olfactory axons during embryonic development. We previously cloned the gene responsible for the X-linked form of the disease encoding a 680 amino acid protein, KAL, which displays the unusual combination of a protease inhibitor domain with fibronectin type III repeats. Previous expression studies by northern blot and RNA in situ hybridization in human and chick indicated that the gene is expressed at very low levels in the olfactory bulb during development. Therefore, low abundance of the protein has hampered a detailed biochemical characterization. By overexpressing both the human and chick KAL cDNAs in eukaryotic cells, we now provide evidence that KAL is a glycosylated peripheral membrane protein with an apparent molecular weight of approximately 100 kDa. We show that this 100 kDa protein is proteolytically processed on the cell membrane to yield a 45 kDa diffusible component, which is detectable with an antisera against the C-terminal part of the protein and binds tightly to cell surfaces. These data provide a first step toward understanding KAL function in neuronal interactions and neurite extension in the olfactory bulb and suggest that KAL might be a diffusible chemoattractant molecule for olfactory axons.
Hum Mol Genet 1996 Aug
PMID:The Kallmann syndrome gene product expressed in COS cells is cleaved on the cell surface to yield a diffusible component. 884 28

Kallmann syndrome is characterized by hypogonadotropic hypogonadism and anosmia. Autosomal dominant, autosomal recessive, and X-linked patterns of transmission have been described. The X-linked form of Kallmann syndrome (XLKS) is the least common of the three modes of inheritance and is caused by mutations in the putative cell adhesion protein, KAL-1. In a large pedigree with XLKS, direct sequencing of the KAL-1 gene revealed a duplication of 11 base pairs in exon 1, resulting in a frameshift and a premature stop at codon 34 of the 680 amino acid protein. The clinical features of the affected individuals in this pedigree provide further evidence in support of the idea that XLKS is associated with neurologic features that are not seen in other forms of the syndrome.
Mol Genet Metab 1998 Sep
PMID:A novel aminoterminal mutation in the KAL-1 gene in a large pedigree with X-linked Kallmann syndrome. 978 96

Gonadotropin Releasing Hormone (GnRH) is a key regulator of reproduction and sexual behaviour. During the last decade, embryological studies have clarified the question of the early development of GnRH-synthesising neurones before the onset of neurosecretion. These studies have revealed the existence of a topographical link between GnRH-synthesising neurones and the embryonic olfactory system, thereby shedding new light on Kallmann syndrome, a developmental disease characterised by the association of hypogonadotropic hypogonadism and anosmia (or hyposmia). Although Kallmann syndrome was identified as an inherited disease in the forties, familial cases of the disease are infrequent. However, the identification, by positional cloning strategies, of the gene underlying the X-chromosome linked form of the disease (KAL-1) has opened the way to molecular pathophysiology. KAL-1 encodes an extracellular glycoprotein of compound modular structure. The protein, named anosmin-1, has been produced in a transfected mammalian cell line and purified. Polyclonal and monoclonal antibodies have been generated, which allowed us to study the distribution of the protein during the period of human organogenesis (4--10 embryonic weeks), by immunohistofluorescence. During this developmental period, anosmin-1 is a locally restricted component of various extracellular matrices (interstitial matrices and basement membranes). Later in embryonic life, KAL-1 expression apparently becomes restricted to definite neuronal populations. Based on the distribution of anosmin-1 in the early olfactory system, the pathogenesis of the olfactory loss and GnRH deficiency in X-linked Kallmann syndrome is discussed.
Mol Cell Endocrinol 2001 Jun 20
PMID:Kallmann syndrome: towards molecular pathogenesis. 1142 Jan 33

Refsum's disease is a neurological syndrome characterized by adult-onset retinitis pigmentosa, anosmia, sensory neuropathy and phytanic acidaemia. Many cases are caused by mutations in peroxisomal oxygenase phytanoyl-CoA 2-hydroxylase (PAHX) which catalyses the initial alpha-oxidation step in the degradation of phytanic acid. Both pro and mature forms of recombinant PAHX were produced in Escherichia coli, highly purified, and shown to have a requirement for iron(II) as a co-factor and 2-oxoglutarate as a co-substrate. Sequence analysis in the light of crystallographic data for other members of the 2-oxoglutarate-dependent oxygenase super-family led to secondary structural predictions for PAHX, which were tested by site-directed mutagenesis. The H175A and D177A mutants did not catalyse hydroxylation of phytanoyl-CoA, consistent with their assigned role as iron(II) binding ligands. The clinically observed P29S, Q176K, G204S, N269H, R275Q and R275W mutants were assayed for both 2-oxoglutarate and phytanoyl-CoA oxidation. The P29S mutant was fully active, implying that the mutation resulted in defective targeting of the protein to peroxisomes. Mutation of Arg-275 resulted in impaired 2-oxoglutarate binding. The Q176K, G204S and N269H mutations caused partial uncoupling of 2-oxoglutarate conversion from phytanoyl-CoA oxidation. The results demonstrate that the diagnosis of Refsum's disease should not solely rely upon PAHX assays for 2-oxoglutarate or phytanoyl-CoA oxidation.
Hum Mol Genet 2001 Sep 01
PMID:Structure-function analysis of phytanoyl-CoA 2-hydroxylase mutations causing Refsum's disease. 1155 34

Spinocerebellar ataxia type-3 or Machado-Joseph disease (SCA3/MJD) is an autosomal dominant neurodegenerative disease caused by triplet nucleotide expansion. The expansion of the polyglutamine tract near the C terminus of the MJD1 gene product, ataxin-3, above a threshold of 40 glutamine repeats causes neuronal loss and degeneration. The expanded ataxin-3 forms aggregates, and nuclear inclusions, within neurons, possibly due to the misfolding of mutant proteins. Here we report upon the behavioral test changes related to truncated and expanded forms of MJD protein (MJDtr) in Drosophila, and show that expanded MJDtr, when expressed in the nervous system, causes characteristic locomotor dysfunction and anosmia. This phenomenon has not been previously reported in humans or in transgenic Drosophila models. In addition, the in vivo expression of the antiapoptotic gene bcl-2 showed no evidence of ameliorating the deleterious effect of MJDtr-Q78s, either in the eye or in the nervous system. The study shows that such Drosophila transgenic models express olfactory dysfunction and ataxic behavior as observed in human patients.
Cell Mol Neurobiol 2004 Feb
PMID:Expression of expanded polyglutamine protein induces behavioral changes in Drosophila (polyglutamine-induced changes in Drosophila). 1504 15


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