Mutation and Polymorphism Analyses of &lt;i&gt;INSL3&lt;/i&gt; and &lt;i&gt;LGR8&lt;/i&gt;/&lt;i&gt;GREAT&lt;/i&gt; in 62 Japanese Patients with Cryptorchidism

Yamazawa, Kazuki; Wada, Yuka; Sasagawa, Isoji; Aoki, Katsuya; Ueoka, Katsuhiko; Ogata, Tsutomu

doi:10.1159/000096089

Cited by 22 publications

(21 citation statements)

References 49 publications

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“…The role of this peptide in the control of testis descent in humans is less clear cut. Mutational analysis of the INSL3 and LGR8/GREAT genes in boys with either unilateral or bilateral cryptorchidism has revealed only a small minority of cases that harbour sequence changes of functional significance (24). A number of substitutions are reported such as Ala60Thr in INSL3 and Ile160Val in LGR8, but functional studies in vitro show no ligand or receptor dysfunction.…”

Section: Transabdominal Phasementioning

confidence: 99%

Factors controlling testis descent

Hughes¹,

Acerini²

2008

European Journal of Endocrinology

139

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Descent of the testis from an intra-abdominal site in foetal life to an extracorporeal location after birth is a mandatory developmental process to ensure that the mature testis promotes normal spermatogenesis. The two phases of transabdominal and inguinoscrotal descent occur approximately during the first and last thirds of gestation respectively. Key anatomical events to release the testis from its urogenital ridge location and to guide the free gonad into the scrotum are the degeneration of the cranio-suspensory ligament and a thickening of the gubernaculum. Androgens play a role in both these processes, particularly with respect to enabling the testis to traverse the inguinal canal in the final phase of descent. Experiments in animals suggest that androgens mediate this effect via the release of calcitonin gene-related peptide by the genitofemoral nerve, but direct evidence for such a mechanism is lacking in humans. The transabdominal phase of descent is under the control of insulinlike 3 (INSL3), a product of the Leydig cells. Definitive evidence of its role in rodent testis descent is illustrated by the phenotype of bilateral cryptorchidism in Insl3K/K null mice. Circulating levels of INSL3 are higher in boys at puberty, are undetectable in girls and are lower in boys with undescended testes. A minority also have a mutation either in the INSL3 gene or affecting its receptor gene, relaxin/insulin-like family peptide receptor 2 (LGRF8). Other factors that may play a role in testis descent include the anti-Mullerian hormone and members of the HOX gene family. Evidence that the prevalence of undescended testis may be increasing provides a phenotypic readout for the effects of postulated chemicals in the environment interfering in some way with the action of factors that control testis descent. Epidemiological studies point to profound geographical variations in prevalence in countries such as Denmark and Finland. Associations have been found with levels of chemicals labelled as endocrine disruptors being higher in breast milk samples from mothers with cryptorchid boys when compared with controls. The adverse effects of these compounds (e.g. bisphenol A) can be replicated in the offspring of dams exposed during pregnancy. A sensitive marker of an anti-androgen effect of a compound is a reduction in the anogenital distance, an anthropometric measurement that is significantly greater in males compared with females. The observation of an association between the anogenital distance in infant boys and the level of pesticides in the urine of their mothers in late gestation indicates that this has the potential to be a useful surrogate marker of the effects of environmental chemicals on testis descent in human population studies. The rightful place for the testis at birth is in the scrotum in order to provide the temperature differential essential for normal spermatogenesis. Appropriate screening programmes and early surgical intervention are the prerequisites to ensure optimal fertility in adulthood and a con...

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Section: Transabdominal Phasementioning

confidence: 99%

Factors controlling testis descent

Hughes¹,

Acerini²

2008

European Journal of Endocrinology

139

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“…Foresta et al [2008] recently reviewed the published data on the INSL3 and LGR8 genes regarding cryptorchidism development. Mutations in these 2 loci have been analyzed in 15 and 7 studies, respectively, including more than 1,500 and almost 1,000 patients with cryptorchidism, respectively, and similar numbers of controls [Koskimies et al, 2000;Krausz et al, 2000;Tomboc et al, 2000;Lim et al, 2001;Marin et al, 2001a, b;Takahashi et al, 2001;Baker et al, 2002;Gorlov et al, 2002;Canto et al, 2003;Ferlin et al, 2003Ferlin et al, , 2006Roh et al, 2003;Feng et al, 2004;Foresta and Ferlin, 2004;Bogatcheva et al, 2007;El Houate et al, 2007;Yamazawa et al, 2007]. Some mutations have been found in both controls and patients and are therefore considered as normal variants, whereas other mutations are detected only in cases [Foresta et al, 2008].…”

Section: Insulin-like Factor 3 and Lgr8 Genesmentioning

confidence: 99%

Morphogenetic Targets and Genetics of Undescended Testis

Massart

Saggese²

2010

Sex Dev

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Although important advances in testicular physiology have been achieved, the aetiology of human cryptorchidism remains mostly unknown. Next to sex steroidal signaling pathways, morphogenetic genes are specifically involved in the testicular descent via gubernacular development. Mutations in the human genes encoding insulin-like factor 3 (INSL3) and its Leu-rich repeat-containing G protein-coupled receptor 8 (LGR8), homeobox A10 (HOXA10), zinc finger 214 (ZNF214) and 215 (ZNF215) have occasionally been identified but do not seem to be a frequent cause of cryptorchidism. On the other hand, common polymorphisms in these genes have recently been investigated as contributing risk factors for idiopathic isolated (nonsyndromic) cryptorchidism.

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“…For SNP genotyping by PCR-RFLP, 17 μl of purified DNA, 2 μl of buffer and 1 μl of the restriction enzyme were incubated for [18][19][20] h. The restriction enzymes used for SNP #5 and #6 were BsmAI (5,000 U/ml, New England BioLabs, Beverly, MA, USA) and MboI (10,000 U/ml, Takara Bio, Otsu, Shiga, Japan), respectively.…”

Section: Pcr-rflpmentioning

confidence: 99%

“…In humans, several candidate genes including androgen receptor (AR) gene [10][11][12], estrogen receptor (ER) gene [13][14][15], insulinlike peptide 3 (INSL3) gene and INSL3 receptor (LGR8) gene [12,[16][17][18] have been investigated for CO. Using single nucleotide polymorphism (SNP) genotyping, which is one of the recent molecular approaches applied to identify candidate genes [19], Yoshida et al [13] reported the association of a specific haplotype (AGATA) including 5 SNPs in the 3' end of the ERα gene (ESR1) with CO in humans.…”

mentioning

confidence: 99%

Analysis of Single Nucleotide Polymorphisms in the 3' Region of the Estrogen Receptor 1 Gene in Normal and Cryptorchid Miniature Dachshunds and Chihuahuas

et al. 2010

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Abstract. This study was performed to examine the distribution of single nucleotide polymorphisms (SNPs) and estimated haplotypes in the canine estrogen receptor (ER) α gene (ESR1) and the association of them with different phenotypes of cryptorchidism (CO) in Miniature Dachshunds and Chihuahuas. Forty CO and 68 normal dogs were used, and CO was classified into unilateral (UCO; n=33) and bilateral CO (BCO; n=5) or into abdominal (ACO; n=16) and inguinal CO (ICO; n=22). Thirteen DNA fragments located in the 70-kb region at the 3' end of ESR1 were amplified by PCR and sequenced to examine 13 SNPs (#1-#13) reported in a canine SNP database. Ten SNPs (#1-#4, #7, #8, #10-#13) were not polymorphic, and 5 new SNPs (#14-#18) were discovered. A common haplotype block in normal, CO and CO phenotypes was identified for an approximately 20-kb region encompassing 4 SNPs (#14-#17). Allele, genotype and haplotype frequencies in CO without classification by phenotype and also in UCO, ACO and ICO phenotypes were not statistically different from the normal group. Significant differences in genotype frequencies and homozygosity for the estimated GTTG haplotype within the block were observed in BCO compared with the normal group, although the number of BCO animals was small. Our results demonstrate that the examined SNPs and haplotypes in the 3' end of canine ESR1 are not associated with unilateral, abdominal and inguinal CO phenotypes and CO per se in Miniature Dachshunds and Chihuahuas. Further studies are necessary to suggest a clear association between the ESR1 SNPs and bilateral CO in dogs. Key words: Cryptorchidism, Dogs, ESR1, Haplotype, Single nucleotide polymorphisms (SNP) (J. Reprod. Dev. 56: [405][406][407][408][409][410] 2010) ryptorchidism (CO) is a developmental defect in male dogs in which descent of one or both testes into the scrotum does not occur by 6 months of age [1]. CO is believed to be heritable [1,2], and the findings of a recent study [3] using carrier and non-carrier parents and their litters in dogs are also supportive of this phenomenon. Clinically, CO manifests in different phenotypes, including unilateral-or bilateral-retention cases and abdominal-or inguinalretention cases. However, the causative or associated genes of canine CO and CO phenotypes are unknown. Except for penilepreputial defects [4], the association between other congenital reproductive diseases and CO has not yet been reported. The incidences of cryptorchidism reported in previous studies of various breeds of dogs range from 1.2 to 10.7 percent [5][6][7][8]. The incidence of cryptorchidism is higher in smaller breeds compared with larger breeds [9].In humans, several candidate genes including androgen receptor (AR) gene [10][11][12], estrogen receptor (ER) gene [13][14][15], insulinlike peptide 3 (INSL3) gene and INSL3 receptor (LGR8) gene [12,[16][17][18] have been investigated for CO. Using single nucleotide polymorphism (SNP) genotyping, which is one of the recent molecular approaches applied to identify candidate genes [19], Yo...

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Mutation and Polymorphism Analyses of <i>INSL3</i> and <i>LGR8</i>/<i>GREAT</i> in 62 Japanese Patients with Cryptorchidism

Cited by 22 publications

References 49 publications

Factors controlling testis descent

Factors controlling testis descent

Morphogenetic Targets and Genetics of Undescended Testis

Analysis of Single Nucleotide Polymorphisms in the 3' Region of the Estrogen Receptor 1 Gene in Normal and Cryptorchid Miniature Dachshunds and Chihuahuas

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