Human male infertility and its genetic causes

Miyamoto, Toshinobu; Minase, Gaku; Shin, Takeshi; Ueda, Hayato; Okada, Hiroshi; Sengoku, Kazuo

doi:10.1002/rmb2.12017

Cited by 62 publications

(51 citation statements)

References 113 publications

(214 reference statements)

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“…E), who presented NOA, increased FSH levels but who unfortunately did not have biopsy results. So far, missense and splice variants in KHLH10 have only been described in association with oligozoospermia in humans (Yatsenko et al ., ; Miyamoto et al ., ) and not in the context of azoospermia or SCO as observed in this study (Patients M1816 and M1811).…”

Section: Resultsmentioning

confidence: 99%

“…Deletions and missense mutations in DMRT1 are associated with a wide spectrum of phenotypes, from XY gonadal dysgenesis to disorders of spermatogenesis such as cryptozoospermia, SCO and meiotic arrest (Tewes et al ., ; Lima et al ., ; Tüttelmann et al ., ). The same variant we found, c.671A>G, has already been reported in two patients with SCO (Tewes et al ., ), whereas missense and splicing variants in KLHL10 have only been associated with oligozoospermia in humans (Yatsenko et al ., ; Miyamoto et al ., ). Hence, we assume that the variant c.671A>G in DMRT1 is causative of SCO in patient M1816, reinforcing the association of this gene with male infertility.…”

Section: Discussionmentioning

confidence: 97%

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Sequence analysis of 37 candidate genes for male infertility: challenges in variant assessment and validating genes

et al. 2019

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Background The routine genetic analysis for diagnosing male infertility has not changed over the last twenty years, and currently available tests can only determine the etiology of 4% of unselected infertile patients. Thus, to create new diagnostic assays, we must better understand the molecular and genetic mechanisms of male infertility. Although next‐generation sequencing allows for simultaneous analysis of hundreds of genes and the discovery of novel candidates related to male infertility, so far only a few gene candidates have enough sound evidence to support the gene–disease relationship. Objective Since complementary studies are required to validate genes, we aimed to analyze the presence of potentially pathogenic rare variants in a set of candidate genes related to azoospermia in a hitherto understudied South American population. Subjects and Methods We performed whole exome sequencing in a group of 16 patients with non‐obstructive azoospermia from Ribeirão Preto, Brazil. Based on a recent systematic review of monogenic causes of male infertility, we selected a set of 37 genes related to azoospermia, Sertoli‐Cell‐Only histology, and spermatogenic arrest to analyze. The identified variants were confirmed by Sanger sequencing, and their functional consequence was predicted by in silico programs. Results We identified potential pathogenic variants in seven genes in six patients. Two variants, c.671A>G (p.(Asn224Ser)) in DMRT1 and c.91C>T (p.(Arg31Cys)) in REC8, have already been described in association with azoospermia. We also found new variants in genes that already have moderate evidence of being linked to spermatogenic failure (TEX15, KLHL10), in genes with limited evidence (DNMT3B, TEX14) and in one novel promising candidate gene that has no evidence so far (SYCE1L). Discussion Although this study included a small number of patients, the process of rationally selecting genes allowed us to detect rare potentially pathogenic variants, providing supporting evidence for validating candidate genes associated with azoospermia.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 97%

Sequence analysis of 37 candidate genes for male infertility: challenges in variant assessment and validating genes

et al. 2019

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“…Genetic abnormalities are in charge of 15%–30% of cases with male infertility (well reviewed in [Coutton, Fissore, Palermo, Stouffs, & Toure, ; Ferlin et al, ; Frank Tüttelmann, ; Hargreave & Elliott, ; Heidary, Saliminejad, Zaki‐Dizaji, & Khorram Khorshid, ; Miyamoto et al, ; Neto, Bach, Najari, Li, & Goldstein, ; Walsh, Pera, & Turek, ]). However, it seems genetic factors responsible for a high percentage of male infertility.…”

Section: Introductionmentioning

confidence: 99%

MicroRNA profiling in spermatozoa of men with unexplained asthenozoospermia

et al. 2019

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Asthenozoospermia (AZS) which is characterised by decreased sperm motility is one of the main causes of male infertility. Recent studies demonstrated altered microRNAs (miRNAs) in total semen, seminal plasma and spermatozoa of asthenozoospermic men. In line with these studies, it was aimed to evaluate the miRNA expression profile in spermatozoa of unexplained asthenozoospermic men. Thirty‐nine cases with idiopathic AZS and 35 fertile and healthy men as control were included. After total RNA extraction from spermatozoa, high‐throughput sequencing technology was employed to display miRNA profiles in spermatozoa samples pooled from AZS cases and healthy controls. Relative quantification by real‐time PCR was performed to validate RNA‐seq results. SNORD48 was used as normaliser gene, and fold change was calculated by 2−ΔΔCt method. Profiling results showed that 18 altered miRNAs in AZS men in comparison to controls. Subsequently, seven miRNAs were selected to validate by RT‐PCR that showed MiR‐888‐3p significantly overexpressed in AZS cases (p = 0.014) in comparison with controls. It seems upregulation of miR‐888‐3p was associated with idiopathic AZS. This finding paves the way to the future investigation on the actual molecular role of miR‐888‐3p in aetiology of AZS.

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“…Infertility is becoming a public health issue in different countries and nations. Male‐factor infertility accounts for a significant proportion of overall infertility among the affected couples (Miyamoto et al, ). Nearly half of all cases of male infertility are thought to be associated with genetic defects (American Urological Association, ; Matzuk & Lamb, ; Lee, Dada, Sabanegh, Carpi, & Agarwal, ).…”

Section: Introductionmentioning

confidence: 99%

Gene alterations and expression spectrum of SPATA33 in nonobstructive azoospermic Iranian men

Monsef

Boroujeni

Totonchi

et al. 2018

Molecular Reproduction Devel

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Genetic abnormalities have been considered a significant cause of male infertility. Increased expression of SPATA33 during the first wave of spermatogenesis indicates its possible association with the meiotic process. The aim of the current study was to investigate the genetic variations in the SPATA33 gene and its expression in patients with nonobstructive azoospermia (NOA). A total of 100 Iranian NOA men with idiopathic infertility were taken as the case group. The control group comprised 100 fertile men who had at least one child. The presence of nucleotide variations was analyzed in both groups using the standard polymerase chain reaction (PCR) sequencing technique. For mRNA and protein expression studies, testicular biopsy specimens from 27 patients were subdivided into three groups: nine obstructive azoospermic patients with hypospermatogenesis as control; nine maturation arrest (MA) and nine Sertoli cell-only syndromes (SCOS) as case groups. The expression of SPATA33 at both mRNA and protein levels was compared among these three groups using the reverse transcription PCR technique, the realtime-PCR technique, and immunohistochemistry. Mutation analysis of the SPATA33 gene revealed five nucleotide changes among the population studied. All but one showed no significant differences between the groups. The genotype distributions of rs112536073A > T in the transcription factor binding site region with heterozygote and homozygote genotypes were significantly different ( p < 0.05) between the two groups. More heterozygotes of this polymorphism were observed in patients, whereas more homozygotes were detected in controls. Accordingly, the current study illustrated that alterations in SPATA33 gene, at least those found in this study, may not impair spermatogenesis in patients with NOA. Reduction of gene expression at the level of mRNA in patients with SCOS can be interpreted by the absence of germ cells in the testicular tissue of these patients.

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Human male infertility and its genetic causes

Cited by 62 publications

References 113 publications

Sequence analysis of 37 candidate genes for male infertility: challenges in variant assessment and validating genes

Sequence analysis of 37 candidate genes for male infertility: challenges in variant assessment and validating genes

MicroRNA profiling in spermatozoa of men with unexplained asthenozoospermia

Gene alterations and expression spectrum of SPATA33 in nonobstructive azoospermic Iranian men

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