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      A Novel Nonsense Mutation of the KAL Gene in Two Brothers withKallmann Syndrome

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          Abstract

          Kallmann syndrome (KS), defined by the association of hypogonadotropic hypogonadism and anosmia or hyposmia, can be caused by mutations in the KAL gene on Xp 22.3. This gene encodes an extracellular matrix glycoprotein called anosmin-1, which belongs to the class of cell adhesion molecules. In the absence of a functional KAL protein, migration of both olfactory and gonadotropin-releasing hormone neurons is arrested. A defective anosmin-1 molecule may also play a role in the development of synkinesia and renal agenesis, which are exclusively seen in the X-linked form of KS. We describe the clinical presentation and molecular diagnosis of the defect in two brothers with KS. An X-linked mode of transmission was assumed on the basis of synkinesia and the presence of oligomenorrhoea in the mother. A novel nonsense mutation was found in exon 13 of the KAL gene, encoding the region of the fourth fibronectin type III repeat of anosmin-1, which results in an apparently nonfunctional truncated protein.

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          Most cited references 4

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          A gene deleted in Kallmann's syndrome shares homology with neural cell adhesion and axonal path-finding molecules.

          Kallmann's syndrome (clinically characterized by hypogonadotropic hypogonadism and inability to smell) is caused by a defect in the migration of olfactory neurons, and neurons producing hypothalamic gonadotropin-releasing hormone. A gene has now been isolated from the critical region on Xp22.3 to which the syndrome locus has been assigned: this gene escapes X inactivation, has a homologue on the Y chromosome, and shows an unusual pattern of conservation across species. The predicted protein has significant similarities with proteins involved in neural cell adhesion and axonal pathfinding, as well as with protein kinases and phosphatases, which suggests that this gene could have a specific role in neuronal migration.
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            Mutations in the homeobox gene HESX1/Hesx1 associated with septo-optic dysplasia in human and mouse.

            During early mouse development the homeobox gene Hesx1 is expressed in prospective forebrain tissue, but later becomes restricted to Rathke's pouch, the primordium of the anterior pituitary gland. Mice lacking Hesx1 exhibit variable anterior CNS defects and pituitary dysplasia. Mutants have a reduced prosencephalon, anopthalmia or micropthalmia, defective olfactory development and bifurcations in Rathke's pouch. Neonates exhibit abnormalities in the corpus callosum, the anterior and hippocampal commissures, and the septum pellucidum. A comparable and equally variable phenotype in humans is septo-optic dysplasia (SOD). We have cloned human HESX1 and screened for mutations in affected individuals. Two siblings with SOD were homozygous for an Arg53Cys missense mutation within the HESX1 homeodomain which destroyed its ability to bind target DNA. These data suggest an important role for Hesx1/HESX1 in forebrain, midline and pituitary development in mouse and human.
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              The candidate gene for the X-linked Kallmann syndrome encodes a protein related to adhesion molecules.

              Kallmann syndrome associates hypogonadotropic hypogonadism and anosmia and is probably due to a defect in the embryonic migration of olfactory and GnRH-synthesizing neurons. The Kallmann gene had been localized to Xp22.3. In this study 67 kb of genomic DNA, corresponding to a deletion interval containing at least part of the Kallmann gene, were sequenced. Two candidate exons, identified by multiparameter computer programs, were found in a cDNA encoding a protein of 679 amino acids. This candidate gene (ADMLX) is interrupted in its 3' coding region in the Kallmann patient, in which the proximal end of the KAL deletion interval was previously defined. A 5' end deletion was detected in another Kallmann patient. The predicted protein sequence shows homologies with the fibronectin type III repeat. ADMLX thus encodes a putative adhesion molecule, consistent with the defect of embryonic neuronal migration.
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                Author and article information

                Journal
                HRE
                Horm Res Paediatr
                10.1159/issn.1663-2818
                Hormone Research in Paediatrics
                S. Karger AG
                1663-2818
                1663-2826
                2000
                2000
                12 October 2000
                : 53
                : 4
                : 207-212
                Affiliations
                Department of Paediatric Endocrinology, University Medical Center Utrecht, Utrecht, The Netherlands
                Article
                23568 Horm Res 2000;53:207–212
                10.1159/000023568
                11044805
                © 2000 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 4, References: 30, Pages: 6
                Categories
                Case Report

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