Frank Tüttelmann

Frank Tüttelmann
University of Münster | WWU · Institute of Reproductive Genetics

Professor

About

173
Publications
25,350
Reads
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3,500
Citations
Introduction
Frank Tüttelmann, MD, was recently appointed director of the newly founded Institute of Reproductive Genetics at the University of Münster, Germany. Besides, he also coordinates the DFG funded Clinical Research Unit ‚Male Germ Cells: from Genes to Function‘ since 2017, which was renewed for a second funding period from 2020-2023. His primary research topic is male infertility and the majority of his publications deals with genetic causes of spermatogenic failure.
Additional affiliations
September 2020 - present
University of Münster
Position
  • Managing Director
March 2008 - August 2020
University of Münster
Position
  • Group Leader
January 2003 - February 2008
University of Münster
Position
  • Medical Doctor

Publications

Publications (173)
Article
Background: The genetic basis of nonobstructive azoospermia is unknown in the majority of infertile men. Methods: We performed array comparative genomic hybridization testing in blood samples obtained from 15 patients with azoospermia, and we performed mutation screening by means of direct Sanger sequencing of the testis-expressed 11 gene (TEX11...
Article
Full-text available
Study question: Are sequence variants in the stromal antigen 3 (STAG3) gene a cause for non-obstructive azoospermia (NOA) in infertile human males? Summary answer: Sequence variants affecting protein function of STAG3 cause male infertility due to meiotic arrest. What is known already: In both women and men, STAG3 encodes for a meiosis-specifi...
Article
Full-text available
The X chromosome is a key player in germ cell development, as has been highlighted for males in previous studies revealing that the mammalian X chromosome is enriched in genes expressed in early spermatogenesis. In this review, we focus on the X chromosome's unique biology as associated with human male infertility. Male infertility is most commonly...
Article
Study question: How can one design and implement a system that provides a comprehensive overview of research results in the field of epi-/genetics of male infertility and germ cells? Summary answer: Working at the interface of literature search engines and raw data repositories, the newly developed Male Fertility Gene Atlas (MFGA) provides a sys...
Article
Male infertility affects ∼7% of men, but its causes remain poorly understood. The most severe form is non-obstructive azoospermia (NOA), which is, in part, caused by an arrest at meiosis. So far, only a few validated disease-associated genes have been reported. To address this gap, we performed whole-exome sequencing in 58 men with unexplained meio...
Article
Background: Recent findings demonstrate that single nucleotide variants can cause non-obstructive azoospermia (NOA). In contrast, copy number variants (CNVs) were only analysed in few studies in infertile men. Some have reported a higher prevalence of CNVs in infertile versus fertile men. Objectives: This study aimed to elucidate if CNVs are ass...
Article
Full-text available
To identify a peculiar genetic combination predisposing to differentiated thyroid carcinoma (DTC), we selected a set of single-nucleotide polymorphisms (SNPs) associated with DTC risk, considering polygenic risk score (PRS), Bayesian statistics, and a machine learning (ML) classifier to describe cases and controls in 3 different datasets. Dataset 1...
Preprint
Non-obstructive azoospermia (NOA) is the most severe form of male infertility and typically incurable with current medicine. Due to the biological complexity of sperm production, defining the genetic basis of NOA has proven challenging, and to date, the most advanced classification of NOA subforms is based on simple description of testis histology....
Article
Although the evolutionary history of the X chromosome indicates its specialization in male fitness, its role in spermatogenesis has largely been unexplored. Currently only three X chromosome genes are considered of moderate-definitive diagnostic value. We aimed to provide a comprehensive analysis of all X chromosome-linked protein-coding genes in 2...
Article
Infertility is a common multifactorial disease and global health problem affecting 10-15% of couples. It can often be overcome by medically assisted reproduction (MAR), offering couples that fail to conceive naturally the chance for parenthood. In half of the couples, the infertility is due to male-factors. Despite advances in the past decade, in t...
Article
Background Crypto- and azoospermia (very few/no sperm in the semen) are main contributors to male factor infertility. Genetic causes for spermatogenic failure (SPGF) include Klinefelter syndrome and Y-chromosomal azoospermia factor microdeletions, and CFTR mutations for obstructive azoospermia (OA). However, the majority of cases remain unexplained...
Article
Full-text available
Study question: We aim to develop, disseminate and implement a minimum data set, known as a core outcome set, for future male infertility research. What is known already: Research into male infertility can be challenging to design, conduct and report. Evidence from randomized trials can be difficult to interpret and of limited ability to inform cl...
Article
In around half of couples affected by infertility, a descriptive diagnosis can be established in the male partner. Genetic analyses can help to establish a causal diagnosis, enable individual counseling and treatment of the couple, and guide treatment decisions. Based on the clinical findings, chromosomal analysis, screening for Y chromosome azoosp...
Article
Purpose Around 70% of infertile men are diagnosed with idiopathic (abnormal semen parameters) or unexplained (normozoospermia) infertility, with the common feature of lacking etiologic. Follicle stimulating hormone (FSH) is essential for initiation and maintenance of spermatogenesis. Certain single nucleotide polymorphisms (SNP) (i.e. FSHB c.-211G>...
Preprint
Full-text available
Germ cells provide the cellular basis for sexual reproduction in multicellular animals. In males, germ cells differentiate into sperm, one of the most morphologically diverse eukaryotic cell types. Owing both to this remarkable diversity and to the rapid evolution of reproduction-related genes, the transcriptional program of male germ cells is wide...
Article
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Background A Delphi consensus was conducted to evaluate the influence of single nucleotide polymorphisms (SNPs) in genes encoding gonadotropin and gonadotropin receptors on clinical ovarian stimulation outcomes following assisted reproductive technology (ART) treatment. Methods Nine experts plus two Scientific Coordinators discussed and amended st...
Article
Testicular derived inhibin B (α/βB dimers) acts in an endocrine manner to suppress pituitary production of follicle stimulating hormone (FSH), by blocking the actions of activins (βA/B/βA/B dimers). Previously, we identified a homozygous genetic variant (c.1079T>C:p.Met360Thr) arising from uniparental disomy of chromosome 2 in the INHBB gene (βB-su...
Article
Full-text available
De novo mutations are known to play a prominent role in sporadic disorders with reduced fitness. We hypothesize that de novo mutations play an important role in severe male infertility and explain a portion of the genetic causes of this understudied disorder. To test this hypothesis, we utilize trio-based exome sequencing in a cohort of 185 inferti...
Article
Background Due to the highly variable clinical phenotype, Klinefelter Syndrome (KS) is underdiagnosed. Objective Assessment of supervised machine learning (sML)-based prediction models for identification of KS among azoospermic patients, and comparison to expert clinical evaluation. Materials and methods Retrospective patient data (karyotype, age...
Article
STUDY QUESTION Do bi-allelic variants in the genes encoding the MSH4/MSH5 heterodimer cause male infertility? SUMMARY ANSWER We detected biallelic, (likely) pathogenic variants in MSH5 (4 men) and MSH4 (3 men) in six azoospermic men, demonstrating that genetic variants in these genes are a relevant cause of male infertility. WHAT IS KNOWN ALREADY...
Article
Full-text available
BACKGROUND Human male infertility has a notable genetic component, including well-established diagnoses such as Klinefelter syndrome, Y-chromosome microdeletions and monogenic causes. Approximately 4% of all infertile men are now diagnosed with a genetic cause, but a majority (60–70%) remain without a clear diagnosis and are classified as unexplain...
Article
Full-text available
Despite the high incidence of male infertility, only 30% of infertile men receive a causative diagnosis. To explore the regulatory mechanisms governing human germ cell function in normal and impaired spermatogenesis (crypto), we performed single-cell RNA sequencing (>30,000 cells). We find major alterations in the crypto spermatogonial compartment...
Article
Study question Which single nucleotide polymorphisms (SNPs) are associated with Follicle stimulating hormone (FSH) levels in men with unexplained infertility and can affect FSH action and spermatogenesis? Summary answer We identified a genomic region at chromosome 11p.14.1, including nine SNPs, that are significantly associated with FSH levels in...
Conference Paper
Study question What is the contribution of the common genetic variation to the development of unexplained male infertility due to severe spermatogenic failure (SPGF)? Summary answer Genetic polymorphisms of key immune and spermatogenesis loci are involved in the etiology of the most severe SPGF cases, defined by Sertoli cell-only (SCO) phenotype....
Article
Full-text available
Male infertility impacts millions of couples yet, the etiology of primary infertility remains largely unknown. A critical element of successful spermatogenesis is maintenance of genome integrity. Here, we present a genomic study of spermatogenic failure (SPGF). Our initial analysis (n = 176) did not reveal known gene-candidates but identified a pot...
Article
Full-text available
Background/aims: Neanderthals, although well adapted to local environments, were rapidly replaced by anatomically modern humans (AMH) for unknown reasons. Genetic information on Neanderthals is limited restricting applicability of standard population genetics. Methods: Here, we apply a novel combination of restricted genetic analyses on preselec...
Preprint
Full-text available
Background: Human male infertility has a notable genetic component, including well-established diagnoses like Klinefelter syndrome, Y-chromosome microdeletions, and monogenic causes. Approximately 4% of all infertile men are now diagnosed with a genetic cause, but a vast majority (60-70%) remain without a clear diagnosis and are classified as unexp...
Article
Full-text available
Mutations affecting the germline can result in infertility or the generation of germ cell tumors (GCT), highlighting the need to identify and characterize the genes controlling germ cell development. The RNA-binding protein and E3 ubiquitin ligase TRIM71 is essential for embryogenesis, and its expression has been reported in GCT and adult mouse tes...
Article
Around 10–15 % of all couples are infertile, rendering infertility a widespread disease. Male and female causes contribute equally to infertility, and, depending on the definition, roughly 1 % to 5 % of all couples experience recurrent miscarriages. In German-speaking countries, recommendations for infertile couples and couples with recurrent misca...
Preprint
Full-text available
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...
Article
STUDY QUESTION Does pituitary response to a GnRH stimulation test differ according to the different FSHB-211 G/T genotypes? SUMMARY ANSWER The promoter polymorphism FSHB-211 G > T affects the pituitary response to exogenous GnRH stimulation by reducing FSH and increasing LH outputs. WHAT IS KNOWN ALREADY The FSHB-211 G > T single nucleotide polym...
Preprint
Full-text available
Introduction De novo mutations (DNMs) are known to play a prominent role in sporadic disorders with reduced fitness ¹ . 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 uni...
Article
Full-text available
Axonemal protein complexes, such as outer (ODA) and inner (IDA) dynein arms, are responsible for the generation and regulation of flagellar and ciliary beating. Studies in various ciliated model organisms have shown that axonemal dynein arms are first assembled in the cell cytoplasm and then delivered into axonemes during ciliogenesis. In humans, m...
Preprint
Full-text available
Despite the high incidence of male infertility, about 70% of infertile men do not receive a causative diagnosis. To gain insights into the regulatory mechanisms governing human germ cell function in normal and impaired spermatogenesis (cryptozoospermic patients, crypto), we combined single cell RNA sequencing (>30.000 cells), proteome, and histomor...
Preprint
Full-text available
Mutations affecting the germline can result in infertility or the generation of germ cell tumors (GCT), highlighting the need to identify and characterize the genes controlling the complex molecular network orchestrating germ cell development. TRIM71 is a stem cell-specific factor essential for embryogenesis, and its expression has been reported in...
Article
Full-text available
Male infertility is a global health issue; yet to a large extent, our knowledge of its causes, impact and consequence is largely unknown. Recent data indicate that infertile men have an increased risk of somatic disorders such as cancer and die younger compared to fertile men. Moreover, several studies point to a significant adverse effect on the h...
Article
Full-text available
Non-obstructive azoospermia (NOA), the lack of spermatozoa in semen due to impaired spermatogenesis affects nearly 1% of men. In about half of cases, an underlying cause for NOA cannot be identified. This study aimed to identify novel variants associated with idiopathic NOA. We identified a nonconsanguineous family in which multiple sons displayed...
Article
STUDY QUESTION When should cystic fibrosis transmembrane conductance regulator (CFTR) mutation analysis be recommended in infertile men based on andrological findings? SUMMARY ANSWER CFTR mutation analysis is recommended in all men with unexplained azoospermia in the presence of normal gonadotropin levels. WHAT IS KNOWN ALREADY While 80–97% of me...
Article
Full-text available
Background: Knowledge about Klinefelter Syndrome (KS) has increased substantially since its first description almost 80 years ago. A variety of treatment options concerning the spectrum of symptoms associated with KS exists, also regarding aspects beyond testicular dysfunction. Nevertheless, the diagnostic rate is still low in relation to prevalen...
Article
Full-text available
Life-long sperm production leads to the assumption that male fecundity remains unchanged throughout life. However, recently it was shown that paternal age has profound consequences for male fertility and offspring health. Paternal age effects are caused by an accumulation of germ cell mutations over time, causing severe congenital diseases. Apart f...
Article
Full-text available
Hypergonadotropic hypogonadism is a major feature of Klinefelter syndrome (KS), assumed to be caused by testicular hormone resistance. It was previously shown that intratesticular testosterone levels in vivo and Leydig cell function in vitro seem to be normal indicating other functional constraints. We hypothesized that impaired testicular vascular...
Article
Azoospermia is observed in 10–15% of men suffering couple infertility. While obstructive (OA) needs to be distinguished from non-obstructive azoospermia (NOA), both entities may be due to congenital or genetically determined disorders as well as acquired disease. NOA is predominantly caused by primary testicular damage, whereas endocrine disease du...
Article
Azoospermia affects 1% of men and it can be the consequence of spermatogenic maturation arrest (MA). Although the etiology of MA is likely to be of genetic origin, only 13 genes have been reported as recurrent potential causes of MA. Exome sequencing in 147 selected MA patients (discovery cohort and two validation cohorts). We found strong evidence...
Article
Full-text available
PurposePrimary angiitis of the central nervous system (PACNS) is a heterogeneous, rare, and poorly understood inflammatory disease. We aimed at non-invasive imaging of activated microglia/macrophages in patients with PACNS by PET-MRI targeting the translocator protein (TSPO) with [18F]DPA-714 to potentially assist differential diagnosis, therapy mo...
Article
Full-text available
The sperm-specific CatSper channel controls the influx of Ca2+ into the flagellum and, thereby, the swimming behavior of sperm. A hallmark of human CatSper is its polymodal activation by membrane voltage, intracellular pH, and oviductal hormones. Whether CatSper is also activated by signaling pathways involving an increase of cAMP and ensuing activ...
Article
Infertility is defined as the inability of a couple to succeed in achieving a spontaneous pregnancy after 1 year. Male and female factors contribute to infertility with approximately 40% each. In the remaining cases factors that affect fertility can be found in both partners. The andrological work-up should be started simultaneously with the gyneco...
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Full-text available
Zusammenfassung Genetische Ursachen sind für etwa 10–20 % der männlichen und 5–10 % der weiblichen In- oder Subfertilität verantwortlich. Bei Männern ist die andrologische Untersuchung Voraussetzung dafür, genetische Ursachen von Spermatogenesestörungen einordnen zu können. Außer Störungen der Geschlechtschromosomen können auch balancierte Chromoso...
Preprint
Interconnecting results of previous OMICs studies is of major importance for identifying novel underlying causes of male infertility. To date, information can be accessed mainly through literature search engines and raw data repositories. However, both have limited capacity in identifying relevant publications based on aggregated research results e...
Preprint
Full-text available
The sperm-specific CatSper channel controls the influx of Ca ²⁺ into the flagellum and, thereby, the swimming behavior of sperm. A hallmark of human CatSper is its polymodal activation by membrane voltage, intracellular pH, and oviductal hormones. Whether CatSper is also activated by signaling pathways involving an increase of cAMP and ensuing acti...
Article
Full-text available
Navigation of sperm in fluid flow, called rheotaxis, provides long-range guidance in the mammalian oviduct. The rotation of sperm around their longitudinal axis (rolling) promotes rheotaxis. Whether sperm rolling and rheotaxis require calcium (Ca 2+) influx via the sperm-specific Ca 2+ channel CatSper, or rather represent passive biomechanical and...
Article
Unexplained infertility affects 2%–3% of reproductive-aged couples. One approach to identifying genes involved in infertility is to study subjects with this clinical phenotype and a de novo balanced chromosomal aberration (BCA). While BCAs may reduce fertility by production of unbalanced gametes, a chromosomal rearrangement may also disrupt or dysr...
Article
During a network meeting on Reproduction in March 2019 in Essen, Germany, more than 70 scientists with the participation of German Research Foundation (DFG) representatives, critically looked at the current situation and future demands on research in reproduction in Germany. These considerations were compiled and presented at the 8th DVR Congress (...
Article
Introduction Supporting and counselling couples with fertility issues prior to starting ART is a multidisciplinary diagnostic and therapeutic challenge. The first German-language interdisciplinary S2k guideline on “Diagnosis and Therapy Before Assisted Reproductive Treatments (ART)” was published in February 2019. The guideline was developed in the...
Preprint
Full-text available
Male infertility affects ~7% of men in Western societies, but its causes remain poorly understood. The most clinically severe form of male infertility is non-obstructive azoospermia (NOA), which is, in part, caused by an arrest at meiosis, but so far only few genes have been reported to cause germ cell arrest in males. To address this gap, whole ex...
Article
Full-text available
Die Ursachen für Unfruchtbarkeit und ungewollte Kinderlosigkeit von Paaren können bei Frau und Mann liegen. Doch die „reproduktive Gesundheit“ des männlichen Geschlechts wurde lange vernachlässigt. Nun setzt die Forschung auf einen Blickwechsel.
Article
Infertilität besteht, wenn trotz regelmäßigen, ungeschützten Geschlechtsverkehrs nach 12 Monaten keine Schwangerschaft eingetreten ist. Die Ursachen für eine ungewollte Kinderlosigkeit liegen zu etwa gleichen Teilen mit je bis zu je 40 % bei Mann und Frau. In den übrigen Fällen finden sich bei beiden Partnern Faktoren, die die Fertilität beeinträch...
Preprint
Full-text available
Children of older fathers have higher risk for certain diseases. Nevertheless, how ageing specifically affects male germ cells is so far not completely understood. In a cohort of 197 healthy men (18-84 years), we found that semen and reproductive parameters remained normal over six decades. Along with an age-dependent increase in telomere length in...