Investigation of a unique male and female sibship with Kallmann's syndrome and 46,XX gonadal dysgenesis with short stature.
A sibship is described where the brother and a sister both have Kallmann's syndrome (anosmia and deficiency of gonadotrophin releasing hormone) and the woman also has streak ovaries. Although there are several conditions that may occur with Kallmann's syndrome, there are no known reports of ovarian dysgenesis being associated with this disorder. Cytogenetic analysis showed no rearrangement or major deletions of the chromosomes. Linkage analysis using informative microsatellite markers predicts that a gene other than KAL1 (at Xp22.3) is implicated in the Kallmann's syndrome manifesting concurrently with ovarian dysgenesis found in this family. (+info)
Developmental and genetic disorders in spermatogenesis.
The most common cause of male infertility is idiopathic. Fresh insights based on genetic and molecular analysis of the human genome permit classification of formerly unexplained disorders in spermatogenesis. In this article, we review new procedures that expand diagnostic and therapeutic approaches to male infertility. Recombinant DNA technology makes it possible to detect specific chromosomal and/or genetic defects among infertile patients. The identification of genes linked to disorders in spermatogenesis and male sexual differentiation has increased exponentially in the past decade. Genetic defects leading to male factor infertility can now be explained at the molecular level, even though the germ cell profile of infertile patients is too variable to permit classification of the clinical phenotype. Increasing knowledge of genes that direct spermatogenesis provides important new information about the molecular and cellular events involved in human spermatogenesis. Molecular analysis of chromosomes and/or genes of infertile patients offers unique opportunities to uncover the aetiology of genetic disorders in spermatogenesis. Increasing numbers of cases, previously classified as idiopathic, can now be diagnosed to facilitate the treatment of infertile men. Advanced knowledge also poses ethical dilemmas, since children conceived with assisted reproductive technologies such as intracytoplasmic sperm injection (ICSI) are at risk for congenital abnormalities, unbalanced complements of chromosomes and male infertility. (+info)
Anosmin-1 is a regionally restricted component of basement membranes and interstitial matrices during organogenesis: implications for the developmental anomalies of X chromosome-linked Kallmann syndrome.
Kallmann syndrome is a developmental disease characterized by gonadotropin-releasing hormone (GnRH) deficiency and olfactory bulb hypoplasia. The gene underlying the X chromosome-linked form, KAL-1, has been identified for several years, yet the pathogenesis of the disease is not understood. By immunohistofluorescence and immunoelectron microscopy, we establish that the KAL-1 encoded protein, anosmin-1, is a transient and regionally restricted component of extracellular matrices during organogenesis in man. Anosmin-1 was detected in the basement membranes and/or interstitial matrices of various structures including bronchial tubes, mesonephric tubules and duct, branches of the ureteric bud, muscular walls of the digestive tract and larger blood vessels, precartilaginous models of skeletal pieces, muscle tendons, head mesenchymes, inner ear, and forebrain subregions. Our results suggest that this protein acts as a local, rather than a long-range, cue during organogenesis. In the olfactory system, anosmin-1 was detected from week 5 onward. The protein was restricted to the olfactory bulb presumptive region and later, to the primitive olfactory bulbs. We therefore suggest that the genetic defect underlying X-linked Kallmann syndrome disrupts the terminal navigation of the early olfactory axons or directly affects the initial steps of olfactory bulb differentiation. The mechanism of the GnRH deficiency is also discussed, relying on the evidence that anosmin-1 is present in the medial walls of the primitive cerebral hemispheres, along the rostro-caudal migratory pathway of the GnRH-synthesizing neurons, at 6 weeks. Finally, the present results strongly suggest that the renal aplasia observed in about one third of the affected individuals results from primary failure of the collecting duct system. (+info)
Episodic leptin release is independent of luteinizing hormone secretion.
Several studies suggest that leptin modulates hypothalamic-pituitary-gonadal axis functions. Leptin may stimulate release of gonadotrophin releasing hormone (GnRH) from the hypothalamus and of gonadotrophins from the pituitary. A synchronicity of luteinizing hormone (LH) and leptin pulses has been described in healthy women and in patients with polycystic ovarian syndrome, suggesting that leptin may modulate the episodic secretion of LH. However, it has not been established whether LH regulates the episodic secretion of leptin. To further examine LH-leptin interactions, we studied the episodic fluctuations of circulating LH and leptin in two patients with Kallmann's syndrome (KS) before and on day 7 of pulsatile GnRH administration, and compared these with those observed in the early follicular phase of 10 regularly menstruating women divided into two control groups according to the body mass index of each patient. To assess episodic hormone secretion, blood samples were collected at 10 min intervals for 6 h, before and on day 7 of GnRH administration in KS patients, and during days 3-7 of the follicular phase in normally cycling women. LH and leptin concentrations were measured in all samples. For pulse analysis, the cluster algorithm was used. Before treatment, an apulsatile pattern with no endogenous LH pulsations was observed in both KS patients. However, leptin pulses were assessed in both women. During GnRH administration, pulsatile LH activity was achieved in both patients with pulse characteristics similar to those of the respective control group. Serum leptin concentrations and leptin pulsatile patterns were not modified. These results suggest that circulating leptin is probably not modulated by pulsatile GnRH-LH secretion. (+info)
Characterization of the two zebrafish orthologues of the KAL-1 gene underlying X chromosome-linked Kallmann syndrome.
The gene underlying X chromosome-linked Kallmann syndrome, KAL-1, has been identified for several years, yet its role in development is still poorly understood. In order to take advantage of the zebrafish as a model in developmental genetics, we isolated the two KAL-1 orthologues, kal1.1 and kal1.2, in this species. Comparison of deduced protein sequences with the human one shows 75.5 and 66.5% overall homology, respectively. The most conserved domains are the whey acidic protein-like domain and the first of four fibronectin-like type III repeats. However, kal1.2 putative protein lacks the basic C-terminal domain (20 residues) found in kal1.1 and KAL-1. The expressions of kal1.1 and kal1.2 were studied in the embryo between 6 and 96 hours post fertilization using whole-mount in situ hybridization. Although a few structures express both genes, kal1.1 and kal1.2 expression patterns are largely non-overlapping. Taken together, these patterns match fairly well those previously reported for human KAL-1 and chicken kal1. As regards the olfactory system, kal1.1 is expressed, from 37 h.p.f. onward, in the presumptive olfactory bulbs, whereas kal1.2 transcript is only detected, from 48 h.p.f., in the epithelium of the nasal cavity. The relevance of the zebrafish as an animal model for studying both the function of KAL-1 in normal development and the developmental failure leading to the olfactory defect in Kallmann syndrome, is discussed. (+info)
A novel mutation of the KAL1 gene in Kallmann syndrome.
Kallmann syndrome is defined by the association of hypogonadotropic hypogonadism and anosmia, for which three modes of transmission have been described: X-linked, autosomal recessive and autosomal dominant. The KAL1 gene, responsible for the X-linked form of the disease, has been isolated and its intron-exon organization determined. We report sequence analysis using PCR-direct sequencing method of the entire coding region and splice site junctions of the KAL1 gene in three males with Kallmann syndrome. We found a novel mutation in one case and no mutation in the other two cases. The mutation consisted of a C to T substitution in exon 1 converting codon 66 (CAG) encoding glutamine into a termination codon (TAG)/(Q66X). As a consequence of this mutation, the function of the KAL1 protein consisting of 680 amino acids was severely truncated so as to be consistent with Kallmann syndrome. As only this patient had unilateral renal hypoplasia among the three cases, this would suggest the existence of KAL1 gene mutation in this abnormality. (+info)
Reactive control of precision grip does not depend on fast transcortical reflex pathways in X-linked Kallmann subjects.
It has been shown that subjects maintain grasp stability by automatically regulating grip force in response to loads applied tangentially to a manipulandum held using a precision grip. Signals from cutaneous mechanoreceptors convey the information necessary for both the initiation and scaling of responses. The central neural pathways that support these grip reactions are unknown. However, the latency of the increase in force is similar to that of 'long-latency' transcortical reflexes recorded from muscles following muscle stretch or electrical stimulation of digital nerves. This study assessed the importance of fast transcortical pathways for reactive grip responses by examining these responses in subjects with X-linked Kallmann's syndrome (XKS). Subjects were selected whose corticospinal projection, as assessed by magnetic brain stimulation, is essentially ipsilateral, and in whom the long-latency reflex components following digital nerve stimulation are only found contralateral to the stimulated side. Despite this anomaly of the fast corticospinal pathway, these XKS subjects responded in the same way as control subjects; grip response latencies were similar and responses were appropriately scaled. However, the non-operating hand of these XKS subjects often mirrored the grip force changes of the operating hand. Reflex force mirroring was most marked during the first 50 ms and the force output was always less than 20 % of that of the operating hand. We conclude, firstly, that somatosensory driven precision grip responses that support grasp stability do not depend on fast conducting corticospinal pathways in these subjects and, secondly, that such responses do not use those 'long-latency' reflex pathways probed by cutaneomuscular reflexes elicited by electrical stimulation of digital nerves. (+info)
A novel mutation of the KAL1 gene in monozygotic twins with Kallmann syndrome.
OBJECTIVE: Kallmann syndrome is defined by the association of hypogonadotropic hypogonadism and anosmia. The KAL1 gene is responsible for the X-linked form of Kallmann syndrome. In this study we describe monozygotic twins with Kallmann syndrome due to the same mutation in the KAL1 gene. DESIGN: We studied male monozygotic twins with Kallmann syndrome. METHODS: We analyzed the KAL1 gene using the PCR-direct sequencing method. The twins' mother was examined for the identified mutation. RESULTS: We identified a 14 bp deletion from codon 419 in exon 9 (Pro419del14) in both KAL1 genes of the twins. This was a novel mutation in the KAL1 gene and was responsible for Kallmann syndrome. As Pro419del14 was not detected in the mother of the twins, Pro419del14 was a germline mutation originating from them. These monozygotic twins showed different LH and FSH responses to LH-RH stimulation and different phenotypes such as complications, physiques and psychiatric characters. CONCLUSIONS: We report an identical KAL1 gene mutation in the monozygotic twins with Kallmann syndrome. As these monozygotic twins showed different phenotypes in some respects, we suggest that factors other than mutations in the KAL1gene affect the symptomatic features of Kallmann syndrome. (+info)