The human<i>RHOX</i>gene cluster: target genes and functional analysis of gene variants in infertile men

Borgmann, Jennifer; Tüttelmann, Frank; Dworniczak, Bernd; Röpke, Albrecht; Song, H. C.; Kliesch, Sabine; Wilkinson, Miles; Laurentino, Sandra; Gromoll, Jörg

doi:10.1093/hmg/ddw313

Cited by 26 publications

(31 citation statements)

References 51 publications

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“…We found that the human RHOXF1 motif (Figure 2b) is likely not utilized by Rhox proteins in mice even though more than 30 Rhox genes exist. Evidently, throughout multiple duplications, Rhox genes seem to have obtained other functionalities in mouse 38 in comparison to the two human RHOX genes that are expressed in reproductive tissues 39 . Therefore, although we found the human RHOXF1 motif to be highly active in mice, this motif is most likely utilized by other proteins such as the mouse specific Obox proteins.…”

Section: Discussionmentioning

confidence: 99%

Beyond accessibility: ATAC-seq footprinting unravels kinetics of transcription factor binding during zygotic genome activation

Bentsen

Goymann

Schultheis

et al. 2019

Preprint

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While footprinting analysis of ATAC-seq data can theoretically enable investigation of transcription factor (TF) binding, the lack of a computational tool able to conduct different levels of footprinting analysis has so-far hindered the widespread application of this method. Here we present TOBIAS, a comprehensive, accurate, and fast footprinting framework enabling genome-wide investigation of TF binding dynamics for hundreds of TFs simultaneously. As a proof-of-concept, we illustrate how TOBIAS can unveil complex TF dynamics during zygotic genome activation (ZGA) in both humans and mice, and explore how zygotic Dux activates cascades of TFs, binds to repeat elements and induces expression of novel genetic elements. TOBIAS is freely available at: https://github.com/loosolab/TOBIAS.

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Section: Discussionmentioning

confidence: 99%

Beyond accessibility: ATAC-seq footprinting unravels kinetics of transcription factor binding during zygotic genome activation

Bentsen

Goymann

Schultheis

et al. 2019

Preprint

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“…Hence, based on these observations the gene remains an important candidate gene for human male infertility. Similar discrepancies in originally published allele frequencies and currently available allele frequencies were found in several other genes including NLRP14 (http://gnomad.broadinstitute.org/variant/11-7060977-A-T) (Westerveld et al 2006), SEPT12 (http://gnomad.broadinstitute.org/variant/16-4833970-C-T) (Lin et al 2012) and RHOXF1 (http://gnomad.broadinstitute.org/variant/X-119243190-C-T) (Borgmann et al 2016).…”

Section: Discussionmentioning

confidence: 99%

A systematic review and standardized clinical validity assessment of male infertility genes

Oud¹,

Voložonoka

Smits

et al. 2018

Preprint

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Study question Which genes are confidently linked to human male infertility? Summary answer Our systematic literature search and clinical validity assessment reveals that a total of 67 genes are currently confidently linked to 81 human male infertility phenotypes. What is known already The discovery of novel male infertility genes is rapidly accelerating with the availability of Next-Generation Sequencing methods, but the quality of evidence for gene-disease relationships varies greatly. In order to improve genetic research, diagnostics and counseling, there is a need for an evidence-based overview of the currently known genes. Study design, size, duration We performed a systematic literature search and evidence assessment for all publications in Pubmed until June 2018 covering genetic causes of male infertility and/or defective male genitourinary development. Participants/materials, setting, methods Two independent reviewers conducted the literature search and included papers on the monogenic causes of human male infertility and excluded papers on genetic association or risk factors, karyotype anomalies and/or copy number variations affecting multiple genes. Next, the quality and the extent of all evidence supporting selected genes was weighed by a standardized scoring method and used to determine the clinical validity of each gene-disease relationship as expressed by the following six categories: no evidence, limited, moderate, strong, definitive or unable to classify. Main results and the role of chance From a total of 23,031 records, we included 1,286 publications about monogenic causes of male infertility leading to a list of 471 gene-disease relationships. The clinical validity of these gene-disease relationships varied widely and ranged from definitive (n=36) to strong (n=12), moderate (n=33), limited (n=86) or no evidence (n=154). A total of 150 gene-disease relationships could not be classified. Limitations, reasons for caution Our literature search was limited to Pubmed. Wider implications of the findings The comprehensive overview will aid researchers and clinicians in the field to establish gene lists for diagnostic screening using validated gene-disease criteria and identify gaps in our knowledge of male infertility. For future studies, the authors discuss the relevant and important international guidelines regarding research related to gene discovery and provide specific recommendations to the field of male infertility. Study funding/competing interest(s) This work was supported by a VICI grant from The Netherlands Organisation for Scientific Research (918-15-667 to JAV).

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“…Several mutations in RHOXF1 and RHOXF2/2B found in patients with severe oligozoospermia stress the importance of these genes in male infertility (14,15). It has been shown that RHOXF2/2B mutations significantly impair the ability to regulate downstream genes such as transcription factors and chaperons from the HSP70 family (15).…”

Section: Rhoxmentioning

confidence: 99%

“…NR5A1 (6,7,8,9) and DMRT1 (10,11) are examples of autosomal genes in which heterozygous mutations are causative. However, sex-chromosomal genes are prime candidates because of their hemizygous state in males and TEX11 (12,13) and RHOX (14,15) are recent examples which, if mutated, cause male infertility.…”

Section: Introductionmentioning

confidence: 99%

MECHANISMS IN ENDOCRINOLOGY: Aberrations of the X chromosome as cause of male infertility

Röpke

Tüttelmann

2017

European Journal of Endocrinology

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Male infertility is most commonly caused by spermatogenetic failure, clinically noted as oligo-or a-zoospermia. Today, in approximately 20% of azoospermic patients, a causal genetic defect can be identified. The most frequent genetic causes of azoospermia (or severe oligozoospermia) are Klinefelter syndrome (47,XXY), structural chromosomal abnormalities and Y-chromosomal microdeletions. Consistent with Ohno's law, the human X chromosome is the most stable of all the chromosomes, but contrary to Ohno's law, the X chromosome is loaded with regions of acquired, rapidly evolving genes, which are of special interest because they are predominantly expressed in the testis. Therefore, it is not surprising that the X chromosome, considered as the female counterpart of the maleassociated Y chromosome, may actually play an essential role in male infertility and sperm production. This is supported by the recent description of a significantly increased copy number variation (CNV) burden on both sex chromosomes in infertile men and point mutations in X-chromosomal genes responsible for male infertility. Thus, the X chromosome seems to be frequently affected in infertile male patients. Four principal X-chromosomal aberrations have been identified so far: (1) aneuploidy of the X chromosome as found in Klinefelter syndrome (47,XXY or mosaicism for additional X chromosomes). (2) Translocations involving the X chromosome, e.g. nonsyndromic 46,XX testicular disorders of sex development (XX-male syndrome) or X-autosome translocations. (3) CNVs affecting the X chromosome. (4) Point mutations disrupting X-chromosomal genes. All these are reviewed herein and assessed concerning their importance for the clinical routine diagnostic workup of the infertile male as well as their potential to shape research on spermatogenic failure in the next years.

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The humanRHOXgene cluster: target genes and functional analysis of gene variants in infertile men

Cited by 26 publications

References 51 publications

Beyond accessibility: ATAC-seq footprinting unravels kinetics of transcription factor binding during zygotic genome activation

Beyond accessibility: ATAC-seq footprinting unravels kinetics of transcription factor binding during zygotic genome activation

A systematic review and standardized clinical validity assessment of male infertility genes

MECHANISMS IN ENDOCRINOLOGY: Aberrations of the X chromosome as cause of male infertility

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