<i>SYCP2</i>translocation-mediated dysregulation and frameshift variants cause human male infertility

Schilit, Samantha L.P.; Menon, Shreya; Friedrich, Corinna; Kammin, Tammy; Wilch, Ellen; Hanscom, Carrie; Jiang, Sizun; Kliesch, Sabine; Talkowski, Michael E.; Tüttelmann, Frank; MacQueen, Amy J.

doi:10.1101/641928

Cited by 10 publications

(13 citation statements)

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“…Two patients were subsequently excluded from this study, because likely causal variants in other genes had been identified in parallel: patient M870 had compound heterozygous variants in STAG3, 23 and patient M1401 had a heterozygous LoF variant in SYCP2 . 24 The prioritized genes in the remaining 58 patients were analyzed with regard to the level of expression in the testes. A literature search was performed to identify genes with previous evidence for an association with infertility in either human or model species.…”

Section: Resultsmentioning

confidence: 99%

“…These results have been reported elsewhere. 6, 23, 24 Among the remaining group of 58 men, we identified three unrelated patients with the same homozygous frameshift variant c.676dup (p.Trp226Leufs*4) in M1AP . Thus, up to 5% of men affected by male infertility, non-obstructive azoospermia and meiotic arrest (3 out of 64) carry causal mutations in M1AP , making this a comparably common reason for germ cell arrest at the spermatocyte stage like TEX11 mutations with 6% (4 out of 64) in this selected patient population.…”

Section: Discussionmentioning

confidence: 99%

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Biallelic mutations in M1AP are a frequent cause of meiotic arrest leading to male infertility

Şg

Nagirnaja

et al. 2019

Preprint

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61Male infertility affects ~7% of men in Western societies, but its causes remain poorly 62 understood. The most clinically severe form of male infertility is non-obstructive azoospermia 63 (NOA), which is, in part, caused by an arrest at meiosis, but so far only few genes have been 64 reported to cause germ cell arrest in males. To address this gap, whole exome sequencing 65 was performed in 60 German men with complete meiotic arrest, and we identified in three 66 unrelated men the same homozygous frameshift variant c.676dup (p.Trp226LeufsTer4) in 67 M1AP, encoding meiosis 1 arresting protein. Then, with collaborators from the International 68Male Infertility Genomics Consortium (IMIGC), we screened a Dutch cohort comprising 99 69 infertile men and detected the same homozygous variant c.676dup in a man with 70 hypospermatogenesis predominantly displaying meiotic arrest. We also identified two 71Portuguese men with NOA carrying likely biallelic loss-of-function (LoF) and missense 72 variants in M1AP among men screened by the Genetics of Male Infertility Initiative (GEMINI). 73Moreover, we discovered a homozygous missense variant p.(Pro389Leu) in M1AP in a 74 consanguineous Turkish family comprising five infertile men. M1AP is predominantly 75 expressed in human and mouse spermatogonia up to secondary spermatocytes and 76 previous studies have shown that knockout male mice are infertile due to meiotic arrest. 77Collectively, these findings demonstrate that both LoF and missense M1AP variants that 78 impair its protein cause autosomal-recessive meiotic arrest, non-obstructive azoospermia 79 and male infertility. In view of the evidence from several independent groups and 80 populations, M1AP should be included in the growing list of validated NOA genes. 81 82We originally selected 64 azoospermic but otherwise healthy male patients who attended the 132 Centre of Reproductive Medicine and Andrology (CeRA), University Hospital Münster 133 (N = 51) or the Clinic for Urology, Pediatric Urology and Andrology, Gießen (N = 13), for 134 couple infertility. This is a subset of all patients included in our large-scale Male Reproductive 135 Genomics (MERGE) study, which currently comprises >800 men including 514 with NOA 136 ( Figure S1). All of the 64 patients were diagnosed with complete bilateral germ cell arrest at 137 the spermatocyte stage after evaluating at least 100 seminiferous tubules in tissue sections 138 of both testes accompanied by a negative TESE outcome, i.e., no sperm could be recovered.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Biallelic mutations in M1AP are a frequent cause of meiotic arrest leading to male infertility

Şg

Nagirnaja

et al. 2019

Preprint

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“…None of the 145-protein altering DNMs occurred in a gene already known for its involvement in autosomal dominant human male infertility. This is not unexpected as only 4 autosomal dominant genes have so far been linked to isolated male infertility in humans 5,9 . Broadly speaking, across genetic disorders, dominantly acting disease genes are usually intolerant to loss-of-function (LoF) mutations, as represented by a high pLI score 10 .…”

Section: Mainmentioning

confidence: 89%

A de novo paradigm for male infertility

Oud¹,

Smits²,

Smith

et al. 2021

Preprint

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De novo mutations (DNMs) are known to play a prominent role in sporadic disorders with reduced fitness. We hypothesize that DNMs play an important role in male infertility and explain a significant fraction of the genetic causes of this understudied disorder. To test this hypothesis, we performed trio-based exome-sequencing in a unique cohort of 185 infertile males and their unaffected parents. Following a systematic analysis, 29 of 145 rare protein altering DNMs were classified as possibly causative of the male infertility phenotype. We observed a significant enrichment of Loss-of-Function (LoF) DNMs in LoF-intolerant genes (p-value=1.00x10-5) as well as predicted pathogenic missense DNMs in missense-intolerant genes (p-value=5.01x10-4). One DNM gene identified, RBM5, is an essential regulator of male germ cell pre-mRNA splicing. In a follow-up study, 5 rare pathogenic missense mutations affecting this gene were observed in a cohort of 2,279 infertile patients, with no such mutations found in a cohort of 5,784 fertile men (p-value=0.009). Our results provide the first evidence for the role of DNMs in severe male infertility and point to many new candidate genes affecting fertility.

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“…None of the 145-protein altering DNMs occurred in a gene already known for its involvement in autosomal dominant human male infertility. This is not unexpected as only 4 autosomal dominant genes have so far been linked to isolated male infertility in humans 5,9 . Broadly speaking, across genetic disorders, dominantly acting disease genes are usually intolerant to loss-offunction (LoF) mutations, as represented by a high pLI score 10 .…”

mentioning

confidence: 89%

“…Mice with a homozygous ENU-induced allele point mutation in RBM5 present with azoospermia and germ cell development arrest at round spermatids. Whilst in mice a homozygous mutation in RBM5 is required to cause azoospermia, this may not be the case in humans as is well-documented for other genes 25 , including the recently reported male infertility gene SYCP2 9 . Of note, RBM5 is a tumour suppressor in the lung 26 , with reduced expression affecting RNA splicing in patients with non-small cell lung cancer 27 .…”

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confidence: 99%

A de novo paradigm for male infertility

Veltman

Oud²,

Smits³

et al. 2021

Preprint

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De novo mutations (DNMs) are known to play a prominent role in many sporadic disorders with reduced fitness. We hypothesize that DNMs play an important role in male infertility and explain a significant fraction of the genetic causes of this understudied disorder. We performed a trio-based exome-sequencing study in a unique cohort of 185 infertile males and their unaffected parents. Following a systematic analysis, 29 of 145 rare protein altering DNMs were classified as possibly causative of the male infertility phenotype. We observed a significant enrichment of Loss-of-Function (LoF) DNMs in LoF-intolerant genes (p-value=1.00x10-5) as well as predicted pathogenic missense DNMs in missense-intolerant genes (p-value=5.01x10-4). One DNM gene identified, RBM5, is an essential regulator of male germ cell pre-mRNA splicing. In a follow-up study, 5 rare pathogenic missense mutations affecting this gene were observed in a cohort of 2,279 infertile patients, with no such mutations found in a cohort of 5,784 fertile men (p-value=0.009). Our results provide the first evidence for the role of DNMs in severe male infertility and point to many new candidate genes affecting fertility.

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SYCP2translocation-mediated dysregulation and frameshift variants cause human male infertility

Abstract: Frank Tüttelmann, M.D., email:Frank.Tuettelmann@ukmuenster.de

Cited by 10 publications

References 100 publications

Biallelic mutations in M1AP are a frequent cause of meiotic arrest leading to male infertility

Biallelic mutations in M1AP are a frequent cause of meiotic arrest leading to male infertility

A de novo paradigm for male infertility

A de novo paradigm for male infertility

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