Molecular genetics of hypospadias and cryptorchidism recent developments

Kalfa, Nicolas; Gaspari, Laura; Ollivier, Matthieu; Philibert, Pascal; Bergougnoux, Anne; Paris, Florentin; Sultan, Charles

doi:10.1111/cge.13432

Cited by 57 publications

(47 citation statements)

References 151 publications

(268 reference statements)

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“…The majority of DSDs are characterized by an atypical combination of chromosomal, gonadal and phenotypic sex and are broadly classified as XX and XY DSDs [5,7]. Though, in some forms of XY DSDs, such as cryptorchidism and hypospadias, the genetic and gonadal/phenotypic sex are in concordance [8]. The prevalence of DSDs in humans is approximately 1.7% of all live births [7,9], whereas the frequency of non-syndromic cryptorchidism alone can be as high as 8% among full-term male births depending on the geographical area [8,10].…”

Section: Introductionmentioning

confidence: 99%

Characterization of a Homozygous Deletion of Steroid Hormone Biosynthesis Genes in Horse Chromosome 29 as a Risk Factor for Disorders of Sex Development and Reproduction

Ghosh

Davis

Rosengren

et al. 2020

Genes

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Disorders of sex development (DSD) and reproduction are not uncommon among horses, though knowledge about their molecular causes is sparse. Here we characterized a ~200 kb homozygous deletion in chromosome 29 at 29.7–29.9 Mb. The region contains AKR1C genes which function as ketosteroid reductases in steroid hormone biosynthesis, including androgens and estrogens. Mutations in AKR1C genes are associated with human DSDs. Deletion boundaries, sequence properties and gene content were studied by PCR and whole genome sequencing of select deletion homozygotes and control animals. Deletion analysis by PCR in 940 horses, including 622 with DSDs and reproductive problems and 318 phenotypically normal controls, detected 67 deletion homozygotes of which 79% were developmentally or reproductively abnormal. Altogether, 8–9% of all abnormal horses were homozygous for the deletion, with the highest incidence (9.4%) among cryptorchids. The deletion was found in ~4% of our phenotypically normal cohort, ~1% of global warmblood horses and ponies, and ~7% of draught breeds of general horse population as retrieved from published data. Based on the abnormal phenotype of the carriers, the functionally relevant gene content, and the low incidence in general population, we consider the deletion in chromosome 29 as a risk factor for equine DSDs and reproductive disorders.

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Section: Introductionmentioning

confidence: 99%

Characterization of a Homozygous Deletion of Steroid Hormone Biosynthesis Genes in Horse Chromosome 29 as a Risk Factor for Disorders of Sex Development and Reproduction

Ghosh

Davis

Rosengren

et al. 2020

Genes

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“…On the contrary, in our study all dogs represented unilateral cryptorchidism with inguinal position of the testis. It is known that molecular mechanisms driving transabdominal and inguinoscrotal migration of the testes are different and androgens play a crucial role in the second phase (Kalfa et al 2019). Thus, we suspect that the observed discrepancy could be caused by different positions of the undescended gonads.…”

Section: Discussionmentioning

confidence: 87%

“…The identification of DNA markers associated with a predisposition to cryptorchidism remains a challenging task in mammals, including dogs (Kalfa et al 2019). The search for such markers in dogs, based on a GWAS, indicated six genomic candidate regions in a Siberian Husky population (Zhao, Onteru, Saatchi, Garrick, & Rothschild, 2014).…”

Section: Discussionmentioning

confidence: 99%

“…Two major phases of this process are distinguished: the transabdominal and inguinoscrotal migrations. The transabdominal phase in dogs occurs in prenatal life, between 35 and 45 days of gestation, while transfer of testes through the inguinal canal starts just after birth and the scrotum is reached by day 35 of postnatal life (Baumans et al 1981;Arrighi et al 2010).The first phase is controlled mainly by insulin-like 3 hormone (INSL3), its receptor relaxin family peptide receptor 2 (RXFP2) and androgens, while androgens play a crucial role in the second phase (Kalfa et al 2019). Cryptorchidism is a complex disorder with a multifactorial background, including genetic (polygenic), environmental and epigenetic factors.…”

Section: Introductionmentioning

confidence: 99%

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Altered expression of CYP17A1 and CYP19A1 in undescended testes of dogs with unilateral cryptorchidism

et al. 2020

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Summary Cryptorchidism is the most common disorder of sex development in dogs and testosterone plays a crucial role in the inguinal phase of the testes descending into the scrotum. The molecular background of impaired testosterone synthesis in the testes of cryptorchid dogs is poorly elucidated. In this study, we analyzed the expression of four genes involved in testicular steroidogenesis (CYP17A1, CYP19A1, HSD3B2 and HSD17B3) in undescended and contralateral scrotal testes from inguinal unilateral cryptorchid dogs (n = 13) and from the scrotal gonads of normal males (n = 15). We found that transcript level of CYP17A1 was significantly increased in inguinal gonads, while the level of CYP19A1 was decreased. For these two genes, we analyzed the methylation level of single CpG sites in the promoter region localized within putative target sites for testicular transcription factors (NUR77, CREB, CAR and HSF2). A correlation between decreased methylation in the promoter of CYP17A1 and its increased transcript level in undescended gonads was observed, but the change in protein level was not significant. We also resequenced the 5ʹ‐flanking region of both genes and two known polymorphic sites, SNP in CYP17A1 and an indel in CYP19A1, were found. However, the distribution of the variants in affected (n = 80) and control (n = 75) dogs was not associated with cryptorchidism. We tentatively conclude that the altered expression of CYP17A1 and CYP19A1 in undescended testes could be caused by their exposure to increased temperature in the body. Furthermore, we showed that the identified polymorphisms cannot be considered markers associated with a predisposition to cryptorchidism.

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“…[4] However, known genetic causes are only found in about 10-30% of cases -leading researchers to suspect that hypospadias has a multifactorial etiology. [5][6][7] The suspected causal factors include iatrogenic factors (e.g. medications taken during pregnancy [8][9][10] or conception via assisted reproductive technologies (ART) [11,12]) and environmental factors (e.g.…”

Section: Introductionmentioning

confidence: 99%

Spatial analysis of hypospadias cases in northern France: Taking clinical data into account.

Prevost

Génin

OCCELLI

et al. 2020

Preprint

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Background Strong evidence for a causal role of environmental factors in a congenital anomaly is still difficult to produce. The collection of statistical data is crucial for gaining a better understanding of the epidemiology and pathophysiology of these anomalies. We aimed to evaluate spatial variations in hypospadias in our region, taking into account of clinical data, and evaluate association to socio-economic and ecological data. Methods All boys with hypospadias born in northern France and seen in Lille University Medical Center (Lille, France) between 1999 and 2012 were included in the analysis. We retrospectively collected geographic data, clinical data (especially known confounding factors associated with an elevated risk of hypospadias), and demographic, socio-economic and ecological data. We analyzed the whole study population and then the subset of boys lacking confounding factors. Results The study sample of 975 cases of hypospadias was characterized by significant spatial heterogeneity (p<0.005) and autocorrelation (p<0.001). We detected two high-incidence clusters that differed with regard to their land use. After the exclusion of 221 patients with confounding factors, two high-incidence clusters with significant disease risks (1.65 and 1.75, respectively; p<0.001) and a significant difference in land use (p<0.001) again appeared. The first cluster contained a higher median [interquartile range] proportion of artificialized land (0.40 [0.22;0.47]) than the remaining “neutral areas” (0.19 [0.08;0.53]) did (p<0.001). Conversely, the second cluster contained a higher median proportion of rural land (0.90 [0.78;0.96]) than the “neutral areas” (0.81 [0.47;0.92]) did (p<0.001). The median deprivation index was significantly lower in the urban cluster (0.47 [0.42;0.55]) and significantly higher in the rural cluster (0.69 [0.56;0.73]) (p<0.001). Conclusions Our results evidenced the heterogeneous spatial distribution of cases of hypospadias in northern France. We identified two clusters with different environmental and social patterns – even after the exclusion of known confounding factors.

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Molecular genetics of hypospadias and cryptorchidism recent developments

Cited by 57 publications

References 151 publications

Characterization of a Homozygous Deletion of Steroid Hormone Biosynthesis Genes in Horse Chromosome 29 as a Risk Factor for Disorders of Sex Development and Reproduction

Characterization of a Homozygous Deletion of Steroid Hormone Biosynthesis Genes in Horse Chromosome 29 as a Risk Factor for Disorders of Sex Development and Reproduction

Altered expression of CYP17A1 and CYP19A1 in undescended testes of dogs with unilateral cryptorchidism

Spatial analysis of hypospadias cases in northern France: Taking clinical data into account.

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