Infertilidade masculina genética rara devido a distúrbio espermático caracterizado pela presença de espermatozóides com morfologia anormal, como macrozoospermia ou globozoospermia, em mais de 85% dos espermatozoides, resultante de mutação em um único gene conhecido por causar teratozoospermia. É um grupo heterogêneo que inclui uma ampla gama de fenótipos anormais de espermatozoides que afetam, única ou simultaneamente, cabeça, pescoço, peça intermediária e/ou cauda.
Introdução
O que você precisa saber de cara
Infertilidade masculina genética rara devido a distúrbio espermático caracterizado pela presença de espermatozóides com morfologia anormal, como macrozoospermia ou globozoospermia, em mais de 85% dos espermatozoides, resultante de mutação em um único gene conhecido por causar teratozoospermia. É um grupo heterogêneo que inclui uma ampla gama de fenótipos anormais de espermatozoides que afetam, única ou simultaneamente, cabeça, pescoço, peça intermediária e/ou cauda.
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Sinais e sintomas
O que aparece no corpo e com que frequência cada sintoma acontece
Características mais comuns
Os sintomas variam de pessoa para pessoa. Abaixo estão as 15 características clínicas mais associadas, ordenadas por frequência.
Linha do tempo da pesquisa
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Genética e causas
O que está alterado no DNA e como passa nas famílias
Genes associados
18 genes identificados com associação a esta condição.
May act as a translational repressor which regulates translation of specific mRNAs by forming a complex with PUM2 that associates with the 3'-UTR of mRNA targets. Capable of interfering with the proadhesive and anti-invasive functions of E-cadherin. Up-regulates the production of MMP14 to promote tumor cell invasion
Cytoplasm, perinuclear regionCytoplasm
Spermatogenic failure 12
An infertility disorder caused by spermatogenesis defects. It results in decreased sperm motility, concentration, and multiple sperm structural defects. Non-obstructive azoospermia, oligozoospermia and oligo-astheno-teratozoospermia are features observed in SPGF12 patients.
Essential for spermiogenesis and male fertility (By similarity). Involved in the formation of sperm acrosome during spermatogenesis
Golgi apparatusCytoplasmic vesicle, secretory vesicle, acrosome
Spermatogenic failure 6
An infertility disorder caused by spermatogenesis defects. The most prominent feature is the malformation of the acrosome, which can be totally absent in most severe cases. Additional features are an abnormal nuclear shape and abnormal arrangement of the mitochondria of the spermatozoon.
Serine/threonine-protein kinase component of the chromosomal passenger complex (CPC), a complex that acts as a key regulator of mitosis. The CPC complex has essential functions at the centromere in ensuring correct chromosome alignment and segregation and is required for chromatin-induced microtubule stabilization and spindle assembly. Also plays a role in meiosis and more particularly in spermatogenesis. Has redundant cellular functions with AURKB and can rescue an AURKB knockdown. Like AURKB,
NucleusChromosomeChromosome, centromereCytoplasm, cytoskeleton, spindle
Spermatogenic failure 5
An infertility disorder caused by spermatogenesis defects. Semen from affected men show close to 100% morphologically abnormal multiflagellar spermatozoa with low motility, oversized irregular heads, and abnormal midpiece and acrosome.
Probable C-mannosyltransferase that mediates C-mannosylation of tryptophan residues on target proteins Required during spermatogenesis for sperm head elongation and acrosome formation (PubMed:21397063, PubMed:21397064). Also plays a role in acrosome attachment to the nuclear envelope (By similarity)
Nucleus inner membrane
Spermatogenic failure 9
An infertility disorder caused by spermatogenesis defects. The most prominent feature is the malformation of the acrosome, which can be totally absent in most severe cases. Additional features are an abnormal nuclear shape and abnormal arrangement of the mitochondria of the spermatozoon.
Involved in sperm flagellum assembly (PubMed:34792097, PubMed:35174165). Plays an essential role in the formation of the radial spokes in flagellum axoneme (By similarity)
Cytoplasm, cytoskeleton, flagellum axonemeCytoplasm, cytoskeleton, cilium axonemeCell projection, ciliumCytoplasm, cytoskeleton
Spermatogenic failure 84
An autosomal recessive male infertility disorder characterized by multiple morphologic abnormalities of the sperm flagella, resulting in severely reduced motility. Some patients also have a reduced sperm count.
Essential for male fertility and sperm mitochondrial sheath formation (By similarity). Required for proper mitochondrial elongation and coiling along the flagellum during the formation of the mitochondrial sheath (By similarity). Facilitates the growth and aggressiveness of neuroblastoma cells (PubMed:30026490). Increases the EZH2 activity and H3K27me3 levels in a RBBP4-dependent manner, and facilitates the enrichment of polycomb repressive complex 2 and H3K27me3 on gene promoters, resulting in
NucleusMitochondrion outer membrane
Spermatogenic failure 90
An autosomal recessive male infertility disorder due to severely reduced progressive motility of sperm.
Structural component of sperm fibrous sheath (By similarity). Required for the formation of the subcellular structure of the sperm flagellum, sperm motility and male fertility (PubMed:35228300)
Cytoplasmic vesicle, secretory vesicle, acrosomeCell projection, cilium, flagellum
Spermatogenic failure 82
An autosomal recessive male infertility disorder characterized by asthenoteratozoospermia and multiple morphologic abnormalities of the sperm flagella.
Essential for the normal assembly and function of sperm flagella axonemes
Cell projection, cilium, flagellum
Spermatogenic failure 65
An autosomal recessive male infertility disorder characterized by asthenoteratozoospermia. Progressive sperm motility is severely reduced or absent due to multiple morphologic abnormalities of the flagella.
Probable adapter protein that bind to and organize the subcellular localization of a variety of membrane proteins containing some PDZ recognition sequence. Involved in the clustering of various receptors, possibly by acting at the receptor internalization level. Plays a role in synaptic plasticity by regulating the trafficking and internalization of AMPA receptors. May be regulated upon PRKCA activation. May regulate ASIC1/ASIC3 channel. Regulates actin polymerization by inhibiting the actin-nuc
Cytoplasm, perinuclear regionMembranePostsynaptic densitySynapse, synaptosomeCytoplasm, cytoskeleton
May regulate MCM3AP phosphorylation through phosphatase recruitment (By similarity). May act as a negative regulator of ABCB1 expression and function through the dephosphorylation of ABCB1 by TFPI2/PPP2R3C complex (PubMed:24333728). May play a role in the activation-induced cell death of B-cells (By similarity)
NucleusCytoplasm
Myoectodermal gonadal dysgenesis syndrome
An autosomal recessive disorder characterized by 46,XY complete gonadal dysgenesis and extragonadal anomalies, including typical facial gestalt, low birth weight, myopathy, rod and cone dystrophy, anal atresia, omphalocele, sensorineural hearing loss, dry and scaly skin, skeletal abnormalities, renal agenesis and neuromotor delay.
May be involved in spermatogenesis
Spermatogenic failure 69
An autosomal recessive male infertility disorder characterized by low sperm concentrations, globozoospermia, and absence of sperm acrosome.
Plays a role in flagellar formation and sperm motility
Cytoplasm, cytoskeleton, flagellum basal body
Spermatogenic failure, X-linked, 3
An infertility disorder characterized by asthenoteratozoospermia. Spermatozoa exhibit multiple morphologic abnormalities, including absent, short, coiled, and irregular-caliber flagella.
Filament-forming cytoskeletal GTPase (Probable). Pro-apoptotic protein involved in LGR5-positive intestinal stem cell and Paneth cell expansion in the intestines, via its interaction with XIAP (By similarity). May also play a role in the regulation of cell fate in the intestine (By similarity). Positive regulator of apoptosis involved in hematopoietic stem cell homeostasis; via its interaction with XIAP (By similarity). Negative regulator of repair and hair follicle regeneration in response to i
CytoplasmCell projection, cilium, flagellumCytoplasmic vesicle, secretory vesicleCell projection, axonCell projection, dendritePerikaryonSynapseMitochondrionNucleus
Spermatogenic failure 99
An autosomal recessive, male infertility disorder characterized by asthenoteratozoospermia with markedly reduced sperm progressive motility, and abnormal sperm morphology. Patient sperm exhibit a thin midpiece, absence of the annulus, and disorganization of the mitochondrial sheath.
Plays a role in acrosome compaction and sperm morphogenesis (PubMed:21911476). Is implicated in sperm-oocyte interaction during fertilization (By similarity)
Cytoplasmic vesicle, secretory vesicle, acrosomeCytoplasmic vesicle, secretory vesicle, acrosome membraneSecreted
Spermatogenic failure 66
An autosomal recessive male infertility disorder characterized by globozoospermia. Affected individuals have a normal sperm count, but spermatozoa are round-headed and lack the acrosome. In addition to pure globozoospermia, some patients have a mixture of acrosomeless spermatozoa and spermatozoa with small or detached acrosomes, which is defined as acrosomal hypoplasia.
Plays a role in intracellular protein trafficking and degradation (PubMed:11707463, PubMed:14570915, PubMed:15358775). May regulate CFTR chloride currents and acid-induced ASIC3 currents by modulating cell surface expression of both channels (By similarity). May also regulate the intracellular trafficking of the ADR1B receptor (PubMed:15358775). May play a role in autophagy (By similarity). Together with MARCHF2 mediates the ubiquitination and lysosomal degradation of CFTR (PubMed:23818989). Ove
CytoplasmGolgi apparatus membraneGolgi apparatus, trans-Golgi network membraneSynapsePostsynaptic densityCell projection, dendrite
Component of the intraflagellar transport (IFT) complex B: together with IFT81, forms a tubulin-binding module that specifically mediates transport of tubulin within the cilium (PubMed:23990561). Binds beta-tubulin via its basic region (PubMed:23990561). Required for ciliogenesis (PubMed:23990561). Essential for flagellogenesis during spermatogenesis (PubMed:33689014)
Cell projection, ciliumCytoplasmic vesicleCell projection, cilium, flagellumCytoplasmic vesicle, secretory vesicle, acrosome
Bardet-Biedl syndrome 22
A form of Bardet-Biedl syndrome, a syndrome characterized by usually severe pigmentary retinopathy, early-onset obesity, polydactyly, hypogenitalism, renal malformation and intellectual disability. Secondary features include diabetes mellitus, hypertension and congenital heart disease. Bardet-Biedl syndrome inheritance is autosomal recessive, but three mutated alleles (two at one locus, and a third at a second locus) may be required for clinical manifestation of some forms of the disease.
Auxiliary component of the CatSper complex, a complex involved in sperm cell hyperactivation. Sperm cell hyperactivation is needed for sperm motility which is essential late in the preparation of sperm for fertilization. Required for CatSper complex targeting and trafficking into the quadrilinear nanodomains. Targets the preassembled CatSper complexes to elongating flagella, where it links the channel-carrying vesicles and motor proteins
Cell projection, cilium, flagellum membrane
Spermatogenic failure 68
An autosomal recessive male infertility disorder characterized by globozoospermia. Affected individuals have a normal sperm count, but spermatozoa are round-headed and lack the acrosome. In addition to pure globozoospermia, some patients have a mixture of acrosomeless spermatozoa and spermatozoa with small or detached acrosomes, which is defined as acrosomal hypoplasia.
Force generating protein of respiratory cilia. Produces force towards the minus ends of microtubules. Dynein has ATPase activity; the force-producing power stroke is thought to occur on release of ADP. Involved in sperm motility; implicated in sperm flagellar assembly (PubMed:34237282). Probable inner arm dynein heavy chain
Cytoplasm, cytoskeleton, cilium axoneme
Spermatogenic failure 56
An autosomal recessive male infertility disorder characterized by severely reduced sperm motility, due to multiple morphologic abnormalities of the flagella.
Medicamentos aprovados (FDA)
2 medicamentos encontrados nos registros da FDA americana.
Variantes genéticas (ClinVar)
228 variantes patogênicas registradas no ClinVar.
Classificação de variantes (ClinVar)
Distribuição de 9 variantes classificadas pelo ClinVar.
Vias biológicas (Reactome)
7 vias biológicas associadas aos genes desta condição.
Diagnóstico
Os sinais que médicos procuram e os exames que confirmam
Tratamento e manejo
Remédios, cuidados de apoio e o que precisa acompanhar
Onde tratar no SUS
Hospitais de referência no Brasil e o protocolo oficial do SUS (PCDT)
🇧🇷 Atendimento SUS — Infertilidade masculina com teratozoospermia por mutação em um único gene
Selecione um estado ou use sua localização para ver resultados.
Dados de DATASUS/CNES, SBGM, ABNeuro e Ministério da Saúde. Sempre confirme a disponibilidade diretamente com o estabelecimento.
Pesquisa ativa
Ensaios clínicos abertos e novidades científicas recentes
Pesquisa e ensaios clínicos
Nenhum ensaio clínico registrado para esta condição.
Publicações mais relevantes
Single-center thorough evaluation and targeted treatment of globozoospermic men.
To characterize, by specific biomarkers and nucleic acid sequencing, the structural and genomic sperm characteristics of partial (PG) and complete globozoospermic (CG) men in order to identify the best reproductive treatment. We assessed spermatozoa from 14 consenting men ultrastructurally, as well as for histone content, sperm chromatin integrity, and sperm aneuploidy. Additional genomic, transcriptomic, and proteomic evaluations were carried out to further characterize the CG cohort. The presence of oocyte-activating sperm cytosolic factor (OASCF) was measured by a phospholipase C zeta (PLCζ) immunofluorescence assay. Couples were treated in subsequent cycles either by conventional ICSI or by ICSI with assisted gamete treatment (AGT) using calcium ionophore (Ionomycin, 19657, Sigma-Aldrich, Saint Louis, MO, USA). Ultrastructural assessment confirmed complete acrosome deficiency in all spermatozoa from CG men. Histone content, sperm chromatin integrity, and sperm aneuploidy did not differ significantly between the PG (n = 4) and CG (n = 10) cohorts. PLCζ assessment indicated a positive presence of OASCF in 4 PG couples, who underwent subsequent ICSI cycles that yielded a 36.1% (43/119) fertilization with a 50% (2/4) clinical pregnancy and delivery rate. PLCζ assessment failed to detect OASCF for 8 CG patients who underwent 9 subsequent ICSI cycles with AGT, yielding a remarkable improvement of fertilization (39/97; 40.2%) (P = 0.00001). Embryo implantation (6/21; 28.6%) and clinical pregnancies (5/7; 71.4%) were also enhanced, resulting in 4 deliveries. Gene mutations (DPY19L2, SPATA16, PICK1) were identified in spermatozoa from CG patients. Additionally, CG patients unable to sustain a term pregnancy had gene mutations involved in zygote development (NLRP5) and postnatal development (BSX). CG patients who successfully sustained a pregnancy had a mutation (PIWIL1) related to sperm phenotype. PLCZ1 was both mutated and underexpressed in these CG patients, regardless of reproductive outcome. Sperm bioassays and genomic studies can be used to characterize this gamete's capacity to support embryonic development and to tailor treatments maximizing reproductive outcome.
Genetic analyses of a large cohort of infertile patients with globozoospermia, DPY19L2 still the main actor, GGN confirmed as a guest player.
Globozoospermia is a rare phenotype of primary male infertility inducing the production of round-headed spermatozoa without acrosome. Anomalies of DPY19L2 account for 50-70% of all cases and the entire deletion of the gene is by far the most frequent defect identified. Here, we present a large cohort of 69 patients with 20-100% of globozoospermia. Genetic analyses including multiplex ligation-dependent probe amplification, Sanger sequencing and whole-exome sequencing identified 25 subjects with a homozygous DPY19L2 deletion (36%) and 14 carrying other DPY19L2 defects (20%). Overall, 11 deleterious single-nucleotide variants were identified including eight novel and three already published mutations. Patients with a higher rate of round-headed spermatozoa were more often diagnosed and had a higher proportion of loss of function anomalies, highlighting a good genotype phenotype correlation. No gene defects were identified in patients carrying < 50% of globozoospermia while diagnosis efficiency rose to 77% for patients with > 50% of globozoospermia. In addition, results from whole-exome sequencing were scrutinized for 23 patients with a DPY19L2 negative diagnosis, searching for deleterious variants in the nine other genes described to be associated with globozoospermia in human (C2CD6, C7orf61, CCDC62, CCIN, DNAH17, GGN, PICK1, SPATA16, and ZPBP1). Only one homozygous novel truncating variant was identified in the GGN gene in one patient, confirming the association of GGN with globozoospermia. In view of these results, we propose a novel diagnostic strategy focusing on patients with at least 50% of globozoospermia and based on a classical qualitative PCR to detect DPY19L2 homozygous deletions. In the absence of the latter, we recommend to perform whole-exome sequencing to search for defects in DPY19L2 as well as in the other previously described candidate genes.
[Detection of DPY19L2 gene mutation in 2 cases of globozoospermia].
To investigate the mutation of the DPY19L2 gene in patients with globozoospermia. We collected the clinical data and peripheral blood from 2 patients with globozoospermia and screened for mutation of the DPY19L2 gene by PCR amplification and DNA sequencing technology. The sperm from the 2 globozoospermia patients were round morphologically under the light microscope, with deeply stained nuclei but no acrosome. Electron microscopy showed the sperm with a large round head but no acrosomal structure, the nuclei enveloped by a single layer of membrane and the cytoplasm dispersed. PCR amplification revealed homozygous deletion of Exon 5, Exon6 and Exon15 in the DPY19L2 gene in both the patients. This study proved that the homozygous mutation of DPY19L2 could lead to globozoospermia, which has an important significance for researches on the molecular mechanisms and gene diagnosis of the disease as well as for clinicians in genetic counseling and treatment.
Knockout of serine-rich single-pass membrane protein 1 (Ssmem1) causes globozoospermia and sterility in male mice†.
Globozoospermia (sperm with an abnormally round head shape) and asthenozoospermia (defective sperm motility) are known causes of male infertility in human patients. Despite many studies, the molecular details of the globozoospermia etiology are still poorly understood. Serine-rich single-pass membrane protein 1 (Ssmem1) is a conserved testis-specific gene in mammals. In this study, we generated Ssmem1 knockout (KO) mice using the CRISPR/Cas9 system, demonstrated that Ssmem1 is essential for male fertility in mice, and found that SSMEM1 protein is expressed during spermatogenesis but not in mature sperm. The sterility of the Ssmem1 KO (null) mice is associated with globozoospermia and loss of sperm motility. To decipher the mechanism causing the phenotype, we analyzed testes with transmission electron microscopy and discovered that Ssmem1-disrupted spermatids have abnormal localization of Golgi at steps eight and nine of spermatid development. Immunofluorescence analysis with anti-Golgin-97 to label the trans-Golgi network, also showed delayed movement of the Golgi to the spermatid posterior region, which causes failure of sperm head shaping, disorganization of the cell organelles, and entrapped tails in the cytoplasmic droplet. In summary, SSMEM1 is crucial for intracellular Golgi movement to ensure proper spatiotemporal formation of the sperm head that is required for fertilization. These studies and the pathway in which SSMEM1 functions have implications for human male infertility and identifying potential targets for nonhormonal contraception.
First custom next-generation sequencing infertility panel in Latin America: design and first results.
To present the development of the first custom gene panel for the diagnosis of male and female infertility in Latin America. We developed a next-generation sequencing (NGS) panel that assesses genes associated with infertility. The panel targeted exons and their flanking regions. Selected introns in the CFTR gene were also included. The FMR1 gene and Y chromosome microdeletions were analyzed with other recommended methodologies. An in-house developed bioinformatic pipeline was applied for the interpretation of the results. Clear infertility phenotypes, idiopathic infertility, and samples with known pathogenic variants were evaluated. A total of 75 genes were selected based on female (primary ovarian insufficiency, risk of ovarian hyperstimulation syndrome, recurrent pregnancy loss, oocyte maturation defects, and embryo development arrest) and male conditions (azoospermia, severe oligospermia, asthenozoospermia, and teratozoospermia). The panel designed was used to assess 25 DNA samples. Two of the variants found were classified as pathogenic and enable the diagnosis of a woman with secondary amenorrhea and a man with oligoasthenoteratozoospermia. Targeted NGS assay metrics resulted in a mean of 180X coverage, with more than 98% of the bases covered ≥20X. Our custom gene sequencing panel designed for the diagnosis of male and female infertility caused by genetic defects revealed the underlying genetic cause of some cases of infertility. The panel will allow us to develop more precise approaches in assisted reproduction.
Publicações recentes
[Detection of DPY19L2 gene mutation in 2 cases of globozoospermia].
Genetic analyses of a large cohort of infertile patients with globozoospermia, DPY19L2 still the main actor, GGN confirmed as a guest player.
First custom next-generation sequencing infertility panel in Latin America: design and first results.
AU040320 deficiency leads to disruption of acrosome biogenesis and infertility in homozygous mutant mice.
DNAH1 gene mutations and their potential association with dysplasia of the sperm fibrous sheath and infertility in the Han Chinese population.
📚 EuropePMCmostrando 9
Single-center thorough evaluation and targeted treatment of globozoospermic men.
Journal of assisted reproduction and genetics[Detection of DPY19L2 gene mutation in 2 cases of globozoospermia].
Zhonghua nan ke xue = National journal of andrologyGenetic analyses of a large cohort of infertile patients with globozoospermia, DPY19L2 still the main actor, GGN confirmed as a guest player.
Human geneticsKnockout of serine-rich single-pass membrane protein 1 (Ssmem1) causes globozoospermia and sterility in male mice†.
Biology of reproductionFirst custom next-generation sequencing infertility panel in Latin America: design and first results.
JBRA assisted reproductionExome sequencing reveals novel causes as well as new candidate genes for human globozoospermia.
Human reproduction (Oxford, England)AU040320 deficiency leads to disruption of acrosome biogenesis and infertility in homozygous mutant mice.
Scientific reportsDNAH1 gene mutations and their potential association with dysplasia of the sperm fibrous sheath and infertility in the Han Chinese population.
Fertility and sterilityA new mutation identified in SPATA16 in two globozoospermic patients.
Journal of assisted reproduction and geneticsAssociações
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Comunidades
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Referências e fontes
Bases de dados externas citadas neste artigo
Publicações científicas
Artigos indexados no PubMed ligados a esta doença no grafo RarasNet — título, periódico e PMID direto da fonte, sem intermediação de IA.
- Single-center thorough evaluation and targeted treatment of globozoospermic men.
- Genetic analyses of a large cohort of infertile patients with globozoospermia, DPY19L2 still the main actor, GGN confirmed as a guest player.
- [Detection of DPY19L2 gene mutation in 2 cases of globozoospermia].
- Knockout of serine-rich single-pass membrane protein 1 (Ssmem1) causes globozoospermia and sterility in male mice†.
- First custom next-generation sequencing infertility panel in Latin America: design and first results.
- AU040320 deficiency leads to disruption of acrosome biogenesis and infertility in homozygous mutant mice.
- DNAH1 gene mutations and their potential association with dysplasia of the sperm fibrous sheath and infertility in the Han Chinese population.
Bases de dados e fontes oficiais
Identificadores e referências canônicas usadas para montar este verbete.
- ORPHA:399808(Orphanet)
- MONDO:0018394(MONDO)
- GARD:17654(GARD (NIH))
- Variantes catalogadas(ClinVar)
- Busca completa no PubMed(PubMed)
- Q2161625(Wikidata)
Dados compilados pelo RarasNet a partir de fontes abertas (Orphanet, OMIM, MONDO, PubMed/EuropePMC, ClinicalTrials.gov, DATASUS, PCDT/MS). Este conteúdo é informativo e não substitui avaliação médica.
Conteúdo mantido por Agente Raras · Médicos e pesquisadores podem colaborar
