Kallmann's Syndrome with a Novel Missense Mutation in the KALI Gene that Modifies the Major Cell Adhesion Site of the Anosmin-1 Protein

Loidi, Lourdes; Castro-Feijóo, Lidia; Barreiro, J; Quinteiro, Celsa; Cabanas, Paloma; Varela, Ramiro; Alonso, A. Bengoa; Domı́nguez, Fernando; Pombo, Manuel

doi:10.1515/jpem.2005.18.6.545

Cited by 8 publications

(6 citation statements)

References 3 publications

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“…Anosmin-1 has also been shown to directly stimulate GnRH neuron migration of mouse GnRH (GN11) neuronal cells in vitro [27] , and knockdown of kal1.1 (not the second gene kal1.2) in zebrafish interferes with GnRH neuron migration [28] . Mutations in KAL1 account for 33-70% of familial cases of KS and 3.1-27.8% of apparently sporadic forms of IHH with anosmia [29] ; [18][19][20][21][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46] . Up to half of males with KAL1 mutations may have unilateral renal agenesis [46] .…”

Section: Kal1mentioning

confidence: 99%

“…Severity was defined by the presence of cryptorchidism, absent LH pulses, and lack of response to exogenous GnRH [34,42] . Reported KAL1 mutations described to date and their relation to the protein structure are reviewed elsewhere, and include deletions, missense, and frameshift mutations [18][19][20][21][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46] . Although three different missense mutations were tested to determine if they affect migration of GnRH neuronal cells (NLT cell), none reduced migration in vitro [27] .…”

Section: Kal1mentioning

confidence: 99%

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Clinical Manifestations of Impaired GnRH Neuron Development and Function

2008

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Gonadotropin-releasing hormone (GnRH) and olfactory neurons migrate together in embryologic development, and disruption of this process causes idiopathic hypogonadotropic hypogonadism (IHH) with anosmia (Kallmann syndrome (KS)). Patients with IHH/KS generally manifest irreversible pubertal delay and subsequent infertility due to deficient pituitary gonadotropins or GnRH. The molecular basis of IHH/KS includes genes that: (1) regulate GnRH and olfactory neuron migration; (2) control the synthesis or secretion of GnRH; (3) disrupt GnRH action upon pituitary gonadotropes, or (4) interfere with pituitary gonadotropin synthesis or secretion. KS patients may also have midline facial defects indicating the diverse developmental functions of genes involved. Most causative genes cause either normosmic IHH or KS except FGFR1, which may cause either phenotype. Recently, several balanced chromosomal translocations have been identified in IHH/KS patients, which could lead to the identification of new disease-producing genes. Although there are two cases reported who have digenic disease, this awaits confirmation in future larger studies. The challenge will be to determine the importance of these genes in the 10–15% of couples with normal puberty who have infertility.

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Section: Kal1mentioning

confidence: 99%

Section: Kal1mentioning

confidence: 99%

Clinical Manifestations of Impaired GnRH Neuron Development and Function

2008

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“…Anosmin-1, defective in the X-linked Kallmann's syndrome, is a 100-kDa component of the ECM, that displays four contiguous fibronectin type III domains (FnIII), which have been found in different proteins involved in cell adhesion such as NCAMs, TAG1 or L1 (Franco et al, 1991;Brummendorf and Rathjen, 1993;Legouis et al, 1993). The first of these FnIII repeats seems to be essential for the cell adhesion capability of this protein (Robertson et al, 2001;Loidi et al, 2005), and is involved in the adhesion and elongation of the neurites of cerebellar neurons (Soussi-Yanicostas et al, 1998). The sequence of anosmin-1 is highly conserved across species, including rodents (Cavia porcellus-guinea pig-ENSCPOG00000013143, ENSCPOP00000011831, Spermophilus tridecemlineatus-squirrel-ENSSTOG00000000380, ENSSTO-P00000000344), although an ortholog in rat and mouse has not been identified to date.…”

Section: Introductionmentioning

confidence: 99%

A novel role for anosmin‐1 in the adhesion and migration of oligodendrocyte precursors

Bribián

Esteban

Clemente

et al. 2008

Developmental Neurobiology

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At embryonic stages of development, oligodendrocyte precursors (OPCs) generated in the preoptic area colonize the entire optic nerve (ON). Different factors controlling migration of ON OPCs have been identified, including secreted growth factors, morphogens and guidance cues, as well as cell adhesion molecules. We have shown previously that the soluble form of the extracellular matrix (ECM) protein anosmin-1, impairs OPC migration induced by FGF-2. In the present work, we show that anosmin-1 is expressed by both migrating OPCs and axons of the retinal ganglion cells in the embryonic ON. In vitro, we observe that OPC migration is strongly impaired by contact with anosmin-1 when used as a substrate and, in contrast to previous results, this effect is independent of FGF-2/FGFR1 signaling. We also show that OPCs preferentially adhere to anosmin-1 when compared with other ECM molecules used as substrates, and that when the endogenous anosmin-1 expressed by OPCs is blocked, OPC adhesion to all the different substrates (including anosmin-1), is significantly reduced. This novel effect of anosmin-1 on cell adhesion is also independent of FGF-2/FGFR1. We finally demonstrate that the blockade of the endogenous anosmin-1 expressed by OPCs impairs their migration. Our data suggest that the endogenous anosmin-1 expressed by OPCs is necessary for the correct adhesion of these cells to the different components of the ECM (including anosmin-1 itself), contributing to the migration of these cells.

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“…22 Mutations in KAL1 account for 33 to 70% of familial cases of KS and 3.1 to 27.8% of apparently sporadic forms of IHH with anosmia. [12][13][14][15][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39] Of males with KAL1 mutations, up to half may have unilateral renal agenesis. 39 Although KS has been described in females, no KAL1 mutations have been described to date, suggesting that KAL1 rarely, if ever, causes phenotypic effects in females.…”

Section: Kal1mentioning

confidence: 99%

The Genetics of Hypogonadotropic Hypogonadism

Bhagavath

Layman²

2007

Semin Reprod Med

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An up-to-date review of the genetic aspects of idiopathic hypogonadotropic hypogonadism (IHH)/Kallmann syndrome (KS) is presented. Because proper development of the neuroendocrine axis must occur for normal puberty and reproductive function, gonadotropin-releasing hormone (GnRH) neuron migration is outlined first, followed by an introduction to the in vitro analysis of GnRH neuron migration. The normal hypothalamic-pituitary-gonadal (HPG) axis at different ages is discussed, along with a brief overview of normal and delayed puberty in both boys and girls. The phenotype of IHH/KS is discussed in detail, with its relation to Mendelian inheritance and chromosomal translocations. The molecular basis of IHH/KS is reviewed, with particular emphasis on the three most common genes ( KAL1, FGFR1, and GNRHR) that possess mutations in these patients. However, all other known genes for which mutations occur are also addressed briefly. The goal of this review is to provide a comprehensive discussion of IHH/KS, and to include both basic science and clinical findings that should allow a more complete understanding of hypothalamic-pituitary neuroendocrinology that is important in puberty and reproduction.

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Kallmann's Syndrome with a Novel Missense Mutation in the KALI Gene that Modifies the Major Cell Adhesion Site of the Anosmin-1 Protein

Cited by 8 publications

References 3 publications

Clinical Manifestations of Impaired GnRH Neuron Development and Function

Clinical Manifestations of Impaired GnRH Neuron Development and Function

A novel role for anosmin‐1 in the adhesion and migration of oligodendrocyte precursors

The Genetics of Hypogonadotropic Hypogonadism

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