Mendelian genetics of male infertility

Hwang, Kathleen; Yatsenko, Alexander N.; Jorgez, Carolina J.; Mukherjee, Sarmistha; Nalam, Roopa L.; Matzuk, Martin M.; Lamb, Dolores J.

doi:10.1111/j.1749-6632.2010.05917.x

Cited by 54 publications

(51 citation statements)

References 164 publications

(190 reference statements)

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“…Genetic studies of male sterility identified the causative mutation in 22 of these genes 12 . Deleterious mutations in the testis-exclusive genes are therefore likely to be under strong negative selection.…”

Section: Resultsmentioning

confidence: 99%

“…Gene annotation analysis and literature searches show that human testis-exclusive genes are significantly enriched in male reproductive processes ( Table 1), and that mutations in some of these genes cause male infertility and sterility 12 . Thus, deleterious mutations in such genes are likely to be under extreme purifying selection.…”

Section: Discussionmentioning

confidence: 99%

“…Such explanations do not account well for lethal and sterility-causing mutations, which are not expected to accumulate in the population since they directly reduce the number of the individual's progeny 11 . However, human infertility has a strong genetic basis and being a very common disorder seems to be a paradox [12][13][14] .…”

mentioning

confidence: 99%

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Reduced selection and accumulation of deleterious mutations in genes exclusively expressed in men

Gershoni

Pietrokovski

2014

Nat Commun

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Sex-limited selection can moderate the elimination of deleterious mutations from the population and contribute to the high prevalence of common human diseases. Accordingly, deleterious mutations in autosomal genes that are exclusively expressed in only one of the sexes undergo sex-limited selection and can reach higher frequencies than mutations similarly selected in both sexes. Here we show that the number of deleterious SNPs in genes exclusively expressed in men is twofold higher than in genes that are selected in both sexes. Additional analyses suggest that the increased number of damaging mutations we found in male-specific genes is due to reduced selection in females. These results are noteworthy since many of these male-specific genes are known to be crucial for male reproduction, and are thus likely to be under strong purifying selection. We suggest that inheritance of male-infertility-causative mutations through unaffected female lineages contributes to the high incidence of male infertility.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Reduced selection and accumulation of deleterious mutations in genes exclusively expressed in men

Gershoni

Pietrokovski

2014

Nat Commun

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“…Studies on mouse models as well as human gene mutation have suggested a correlation between genetic causes (e.g. chromosomal aberrations and single gene mutation) and male infertility (Cooke & Saunders 2002, Ferlin et al 2007, Walsh et al 2009, Hwang et al 2010, Shelling 2010. For male infertility with a normal genetic background, stem cell therapy to generate male gametes may represent a promising treatment strategy.…”

Section: Introductionmentioning

confidence: 99%

Generation of male differentiated germ cells from various types of stem cells

Hou

Yang

et al. 2014

Reproduction

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Infertility is a major and largely incurable disease caused by disruption and loss of germ cells. It affects 10-15% of couples, and male factor accounts for half of the cases. To obtain human male germ cells 'especially functional spermatids' is essential for treating male infertility. Currently, much progress has been made on generating male germ cells, including spermatogonia, spermatocytes, and spermatids, from various types of stem cells. These germ cells can also be used in investigation of the pathology of male infertility. In this review, we focused on advances on obtaining male differentiated germ cells from different kinds of stem cells, with an emphasis on the embryonic stem (ES) cells, the induced pluripotent stem (iPS) cells, and spermatogonial stem cells (SSCs). We illustrated the generation of male differentiated germ cells from ES cells, iPS cells and SSCs, and we summarized the phenotype for these stem cells, spermatocytes and spermatids. Moreover, we address the differentiation potentials of ES cells, iPS cells and SSCs. We also highlight the advantages, disadvantages and concerns on derivation of the differentiated male germ cells from several types of stem cells. The ability of generating mature and functional male gametes from stem cells could enable us to understand the precise etiology of male infertility and offer an invaluable source of autologous male gametes for treating male infertility of azoospermia patients.

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“…Classic examples of genes, the mutation of which affect male fertility, are the CF transmembrane receptor gene and the androgen receptor gene [15,16]. Mutations in the CFTR gene may lead to congenital bilateral absence of the vas deferens and obstructive azoospermia (observed in approx.…”

mentioning

confidence: 99%

Genetic aspects of male infertility

Witczak¹,

Klusek²,

Klusek³

2014

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Currently, infertility affects up to 140 million people worldwide. It is considered that the male factor is responsible for nearly a half of problems in obtaining pregnancy. Increasingly, infertility treatment clinics, as well as standard examinations, also offer genetic tests in the diagnostics of the male infertility factor, such as: karyotype analysis, detection of Y chromosome microdeletions, and examination of the chromosome composition of sperm by the fluorescent in situ hybridisation method (FISH). Genetic factors, defined to date, which cover both chromosomal aberrations and monogenic disorders, are responsible for approximately 10-15% of cases of male infertility. Usually, their phenotypic manifestations are disorders in spermatogenesis, structural changes in the genital organs (e.g. reduced size of the testicles), or sperm dysfunction. Molecular studies intensively carried out in the area of diagnostics and treatment of infertility indicate an increasingly large number of relationships between genetic factors and fertility; however, many genes related with human fertility still remain unidentified. StreszczenieNiepłodność dotyka obecnie ok. 140 mln ludzi na świecie. Uważa się, że męski czynnik odpowiada za blisko połowę problemów z uzyskaniem ciąży. Coraz częściej kliniki leczenia niepłodności poza standardowymi badaniami oferują również testy genetyczne w diagnostyce męskiego czynnika niepłodności, takie jak: analiza kariotypu, określanie mikrodelecji chromosomu Y oraz badanie składu chromosomowego plemników metodą FISH (fluorescence in situ hybridization). Zdefiniowane obecnie czynniki genetyczne, obejmujące zarówno aberracje chromosomowe, jak i zmiany monogeniczne, odpowiadają za ok. 10-15% przypadków niepłodności męskiej. Fenotypowo przejawiają się one zwykle w postaci zaburzeń spermatogenezy, strukturalnych zmian w obrębie genitaliów (np. zmniejszenie rozmiaru jąder) czy zaburzeń funkcji plemników. Badania molekularne prowadzone intensywnie w dziedzinie diagnostyki i leczenia niepłodności wykazują coraz więcej zależności pomiędzy czynnikami genetycznymi a płodnością, ale wiele genów związanych z płodnością człowieka pozostaje wciąż niezidentyfikowanych.

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Mendelian genetics of male infertility

Cited by 54 publications

References 164 publications

Reduced selection and accumulation of deleterious mutations in genes exclusively expressed in men

Reduced selection and accumulation of deleterious mutations in genes exclusively expressed in men

Generation of male differentiated germ cells from various types of stem cells

Genetic aspects of male infertility

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