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

doi:10.1016/0092-8674(91)90193-3

Cell

Volume 67, Issue 2, 18 October 1991, Pages 423-435

https://doi.org/10.1016/0092-8674(91)90193-3 Get rights and content

Summary

Kallmann syndrome associates hypogonadotropic hypogonadismand 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 111 repeat. ADMLX thus encodes a putative adhesion molecule, consistent with the defect of embryonic neuronal migration.

References (86)

AlbertsenH.M. et al.
Construction and characterization of a yeast artificial chromosome library containing seven haploid human genome equivalents
AltschulS.F.
Amino acid substitution matrices from an information theoric perspective
J. Mol. Biol.
(1991)
AltschulS.F. et al.
Protein database searches for multiple alignments
AltschulS.F. et al.
Basic local alignment search tool
J. Mol. Biol.
(1990)
AndrewsP.W.
Retinoic acid induces neuronal differentiation of a cloned human embryonal carcinoma cell line in vitro
Dev. Biol.
(1984)
ArakiK. et al.
Novel peptide inhibitor (SPAI) of Na⁺,K⁺-ATPase from porcine intestine
Biochem. Biophys. Res. Commun.
(1989)
AurivilliusM. et al.
The cell adhesion molecule Cell-Cam 105 is an ecto-ATPase and a member of the immunoglobulin superfamily
FEBS Lett.
(1990)
BairochA.
PROSITE: a dictionary of sites and patterns in proteins
Nucl. Acids Res.
(1991)
BallabioA. et al.
Deletions of the steroid sulfatase gene in classical X-linked ichthyosis and in X-linked ichthyosis associated with Kallmann syndrome
Hum. Genet.
(1987)
BallabioA. et al.
Contiguous gene syndromes due to deletions in the distal short arm of the human X chromosome

BallabioA. et al.

Two families of low-copy number repeats are interspersed on Xp22.3: implications for the high frequency of deletions in this region

Genomics

(1990)

Bellanné-ChantelotC. et al.

A test case for physical mapping of human genome by repetitive sequence fingerprints: construction of a physical map of a 420kb YAC subcloned into cosmids

Nucl. Acids Res.

(1991)

BenianG.M. et al.

Sequence of an unusually large protein implicated in regulation of myosin activity in C. elegans

Nature

(1989)

BoguskiM. et al.

Molecular sequence databases and their uses

BoulouxP.M. et al.

A dinucleotide repeat polymorphism at the Kallmann locus

Nucl. Acids Res.

(1991)

BrümmendorfT. et al.

Neural cell recognition molecule F11: homology with fibronectin type III and immunoglobulin type C domains

Neuron

(1989)

ChangS. et al.

Extension of neurites on axons is impaired by antibodies against specific neural cell surface glycoproteins

J. Cell Biol.

(1987)

ChaussainJ.L. et al.

Mode of inheritance in familial cases of primary gonadotropic deficiency

Hormone Res.

(1988)

ClaverieJ.M. et al.

k-tuple frequency analysis: from intron/exon discrimination to T-cell epitope mapping

Meth. Enzymol.

(1990)

CoulsonA. et al.

Preparation of DNA from lambda clones

CoxE.C. et al.

Axonal guidance in the chick visual system: posterior tectal membranes induce collapse of growth cones from the temporal retina

Neuron

(1990)

CunninghamB.A. et al.

Neural cell adhesion molecule: structure immunoglobulin-like domains, cell surface modulation, and alternative RNA splicing

Science

(1987)

DaviesJ.A. et al.

Isolation from chick somites of a glycoprotein fraction that causes collapse of dorsal root ganglion growth cones

Neuron

(1990)

DearT.N. et al.

The WDNM1 gene product is a novel member of the “four-disulphide Core” family of proteins

Biochem. Biophys. Res. Commun.

(1991)

de MorsierG.

Etudes sur les dysraphies cranio-encéphaliques

Schweiz Arch. Neurol. Psychiat.

(1954)

EdelmanG.M. et al.

Cell adhesion molecules: implications for a molecular histology

Annu. Rev. Biochem.

(1991)

EricksonH.P. et al.

A six-armed oligomer isolated from cell surface fibronectin preparations

Nature

(1984)

FischerG. et al.

Neurite outgrowth patterns in cerebellar microexplant cultures are affected by antibodies to the cell surface glycoprotein L1

J. Neurosci.

(1986)

FogertyF.J. et al.

Inhibition of binding of fibronectin to matrix assembly sites by anti-integrin (α5 β1) antibodies

J. Cell Biol.

(1990)

FurleyA.J. et al.

The axonal glycoprotein TAG-1 is an immunoglobulin superfamily member with neurite outgrowth-promoting activity

Cell

(1990)

GennariniG. et al.

Transfected F3/F11 neuronal cell surface protein mediates intercellular adhesion and promotes neurite outgrowth

Neuron

(1991)

GowerH.J. et al.

Alternative splicing generates a secreted form of N-CAM in muscle and brain

Cell

(1988)

GrumetM. et al.

Structure of a new nervous system glycoprotein, Nr-CAM, and its relationship to subgroups of neural cell adhesion molecules

J. Cell Biol.

(1991)

HarrelsonA.L. et al.

Growth cone guidance in insects: fasciclin II is a member of the immunoglobulin superfamily

Science

(1988)

HowleyP.M. et al.

A rapid method for detecting and mapping homology between heterologous DNAs

J. Biol. Chem.

(1979)

JonesF.S. et al.

A detailed structural model of cytotactin: protein homologies alternative RNA splicing, and binding regions

JonesJ. et al.

Olfacto-genital dysplasia in the female

Obstet. Gynecol. Annu.

(1976)

JonesP.C..T.

A contractile protein model of cell adhesion

Nature

(1966)

KallmannF.J. et al.

The genetic aspects of primary eunuchoidism

Am. J. Mental Deficiency

(1944)

KleinP. et al.

Prediction of protein structural class from the amino acid sequence

Biopolymers

(1986)

KlingmüllerD. et al.

Magnetic resonance imaging of the brain in patients with anosmia and hypothalamic hypogonadism (Kallmann's syndrome)

J. Clin. Endocrinol. Metab.

(1987)

KnowltonR.G. et al.

An extremely polymorphic locus on the short arm of the human X chromosome with homology to the long arm of the Y chromdsome

Nucl. Acids Res.

(1989)

KozakM.

Point mutations define a sequence flanking the AUG initiator codon that modulates translation by eukaryotic ribosomes

Cell

(1986)

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In humans, ANOS1 is located on the short arm of the X-chromosome (Xp22.3) and encodes for an extracellular matrix glycoprotein ANOSMIN-1. The structure has parallels to neuronal cell adhesion molecules and serine protease inhibitors (Franco et al., 1991; Legouis et al., 1991). The phenotype of Kallmann syndrome has two main characteristics, (a) anosmia, the inability to smell, and (b) hypogonadotropic hypogonadism (Kallmann et al., 1944).
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It stands to reason that pathogenic variants in a gene encoding a ligand and its receptor could lead to a similar phenotype. For example, protein products of ANOS1(Legouis et al. 1991; Franco et al. 1991) and FGF8(Falardeau et al. 2008) both bind to the FGFR1 protein and utilize heparan sulfate (involving a sulfotransferase gene--HS6ST1(Tornberg et al. 2011)). Pathogenic variants in other FGF pathway genes have also been substantiated in patients in nHH/KS, including FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 (Miraoui et al., 2013), as well as FGF8(Falardeau et al. 2008) (Table 2).
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Cell

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

Summary

Construction and characterization of a yeast artificial chromosome library containing seven haploid human genome equivalents

Amino acid substitution matrices from an information theoric perspective

J. Mol. Biol.

Protein database searches for multiple alignments

Basic local alignment search tool

J. Mol. Biol.

Retinoic acid induces neuronal differentiation of a cloned human embryonal carcinoma cell line in vitro

Dev. Biol.

Novel peptide inhibitor (SPAI) of Na+,K+-ATPase from porcine intestine

Biochem. Biophys. Res. Commun.

The cell adhesion molecule Cell-Cam 105 is an ecto-ATPase and a member of the immunoglobulin superfamily

FEBS Lett.

PROSITE: a dictionary of sites and patterns in proteins

Nucl. Acids Res.

Deletions of the steroid sulfatase gene in classical X-linked ichthyosis and in X-linked ichthyosis associated with Kallmann syndrome

Hum. Genet.

Contiguous gene syndromes due to deletions in the distal short arm of the human X chromosome

Two families of low-copy number repeats are interspersed on Xp22.3: implications for the high frequency of deletions in this region

Genomics

A test case for physical mapping of human genome by repetitive sequence fingerprints: construction of a physical map of a 420kb YAC subcloned into cosmids

Nucl. Acids Res.

Sequence of an unusually large protein implicated in regulation of myosin activity in C. elegans

Nature

Molecular sequence databases and their uses

A dinucleotide repeat polymorphism at the Kallmann locus

Nucl. Acids Res.

Neural cell recognition molecule F11: homology with fibronectin type III and immunoglobulin type C domains

Neuron

Extension of neurites on axons is impaired by antibodies against specific neural cell surface glycoproteins

J. Cell Biol.

Mode of inheritance in familial cases of primary gonadotropic deficiency

Hormone Res.

k-tuple frequency analysis: from intron/exon discrimination to T-cell epitope mapping

Meth. Enzymol.

Preparation of DNA from lambda clones

Axonal guidance in the chick visual system: posterior tectal membranes induce collapse of growth cones from the temporal retina

Neuron

Neural cell adhesion molecule: structure immunoglobulin-like domains, cell surface modulation, and alternative RNA splicing

Science

Isolation from chick somites of a glycoprotein fraction that causes collapse of dorsal root ganglion growth cones

Neuron

The WDNM1 gene product is a novel member of the “four-disulphide Core” family of proteins

Biochem. Biophys. Res. Commun.

Etudes sur les dysraphies cranio-encéphaliques

Schweiz Arch. Neurol. Psychiat.

Cell adhesion molecules: implications for a molecular histology

Annu. Rev. Biochem.

A six-armed oligomer isolated from cell surface fibronectin preparations

Nature

Neurite outgrowth patterns in cerebellar microexplant cultures are affected by antibodies to the cell surface glycoprotein L1

J. Neurosci.

Inhibition of binding of fibronectin to matrix assembly sites by anti-integrin (α5 β1) antibodies

J. Cell Biol.

The axonal glycoprotein TAG-1 is an immunoglobulin superfamily member with neurite outgrowth-promoting activity

Cell

Transfected F3/F11 neuronal cell surface protein mediates intercellular adhesion and promotes neurite outgrowth

Neuron

Alternative splicing generates a secreted form of N-CAM in muscle and brain

Cell

Structure of a new nervous system glycoprotein, Nr-CAM, and its relationship to subgroups of neural cell adhesion molecules

J. Cell Biol.

Growth cone guidance in insects: fasciclin II is a member of the immunoglobulin superfamily

Science

A rapid method for detecting and mapping homology between heterologous DNAs

J. Biol. Chem.

A detailed structural model of cytotactin: protein homologies alternative RNA splicing, and binding regions

Olfacto-genital dysplasia in the female

Obstet. Gynecol. Annu.

A contractile protein model of cell adhesion

Nature

The genetic aspects of primary eunuchoidism

Am. J. Mental Deficiency

Prediction of protein structural class from the amino acid sequence

Biopolymers

Magnetic resonance imaging of the brain in patients with anosmia and hypothalamic hypogonadism (Kallmann's syndrome)

J. Clin. Endocrinol. Metab.

An extremely polymorphic locus on the short arm of the human X chromosome with homology to the long arm of the Y chromdsome

Novel peptide inhibitor (SPAI) of Na⁺,K⁺-ATPase from porcine intestine