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Hsueh lab

HPMR

DENN domain containing 1A

OKDB#: 4434

Symbols:	DENND1A	Species:	human
Synonyms:	FAM31A, KIAA1608	Locus:	9q33.3 in Homo sapiens
HPMR

For retrieval of Nucleotide and Amino Acid sequences please go to: OMIM Entrez Gene
Mammalian Reproductive Genetics Endometrium Database Resource Orthologous Genes UCSC Genome Browser GEO Profiles ^new! Amazonia (transcriptome data) ^new!
R-L INTERACTIONS MGI

General Comment

Connecdenn, a novel DENN domain-containing protein of neuronal clathrin-coated vesicles functioning in synaptic vesicle endocytosis. Allaire PD et al. Clathrin-coated vesicles (CCVs) are responsible for the endocytosis of multiple cargo, including synaptic vesicle membranes. We now describe a new CCV protein, termed connecdenn, that contains an N-terminal DENN (differentially expressed in neoplastic versus normal cells) domain, a poorly characterized protein module found in multiple proteins of unrelated function and a C-terminal peptide motif domain harboring three distinct motifs for binding the alpha-ear of the clathrin adaptor protein 2 (AP-2). Connecdenn coimmunoprecipitates and partially colocalizes with AP-2, and nuclear magnetic resonance and peptide competition studies reveal that all three alpha-ear-binding motifs contribute to AP-2 interactions. In addition, connecdenn contains multiple Src homology 3 (SH3) domain-binding motifs and coimmunoprecipitates with the synaptic SH3 domain proteins intersectin and endophilin A1. Interestingly, connecdenn is enriched on neuronal CCVs and is present in the presynaptic compartment of neurons. Moreover, connecdenn has a uniquely stable association with CCV membranes because it resists extraction with Tris and high-salt buffers, unlike most other CCV proteins, but it is not detected on purified synaptic vesicles. Together, these observations suggest that connecdenn functions on the endocytic limb of the synaptic vesicle cycle. Accordingly, disruption of connecdenn interactions with its binding partners through overexpression of the C-terminal peptide motif domain or knock down of connecdenn through lentiviral delivery of small hairpin RNA both lead to defects in synaptic vesicle endocytosis in cultured hipocampal neurons. Thus, we identified connecdenn as a component of the endocytic machinery functioning in synaptic vesicle endocytosis, providing the first evidence of a role for a DENN domain-containing protein in endocytosis.////////////////Ultraconserved elements in the human genome: association and transmission analyses of highly constrained single-nucleotide polymorphisms. Chiang CW et al. (2013) Ultraconserved elements in the human genome likely harbor important biological functions as they are dosage sensitive and are able to direct tissue-specific expression. Because they are under purifying selection, variants in these elements may have a lower frequency in the population but a higher likelihood of association with complex traits. We tested a set of highly constrained SNPs (hcSNPs) distributed genome-wide among ultraconserved and nearly ultraconserved elements for association with seven traits related to reproductive (age at natural menopause, number of children, age at first child, and age at last child) and overall [longevity, body mass index (BMI), and height] fitness. Using up to 24,047 European-American samples from the National Heart, Lung, and Blood Institute Candidate Gene Association Resource (CARe), we observed an excess of associations with BMI and height. In an independent replication panel the most strongly associated SNPs showed an 8.4-fold enrichment of associations at the nominal level, including three variants in previously identified loci and one in a locus (DENND1A) previously shown to be associated with polycystic ovary syndrome. Finally, using 1430 family trios, we showed that the transmissions from heterozygous parents to offspring of the derived alleles of rare (frequency ≤ 0.5%) hcSNPs are not biased, particularly after adjusting for the rates of genotype missingness and error in the data. The lack of transmission bias ruled out an immediately and strongly deleterious effect due to the rare derived alleles, consistent with the observation that mice homozygous for the deletion of ultraconserved elements showed no overt phenotype. Our study also illustrated the importance of carefully modeling potential technical confounders when analyzing genotype data of rare variants.//////////////////

NCBI Summary: Clathrin (see MIM 118955)-mediated endocytosis is a major mechanism for internalization of proteins and lipids. Members of the connecdenn family, such as DENND1A, function as guanine nucleotide exchange factors (GEFs) for the early endosomal small GTPase RAB35 (MIM 604199) and bind to clathrin and clathrin adaptor protein-2 (AP2; see MIM 601024). Thus, connecdenns link RAB35 activation with the clathrin machinery (Marat and McPherson, 2010 [PubMed 20154091]).[supplied by OMIM, Nov 2010]

General function

Extracellular binding protein, Receptor

Comment

Ultraconserved Elements in the Human Genome: Association and Transmission Analyses of Highly Constrained SNPs. Chiang CW et al. Ultraconserved elements in the human genome likely harbor important biological functions as they are dosage sensitive and are able to direct tissue-specific expression. Because they are under purifying selection, variants in these elements may have a lower frequency in the population but a higher likelihood of association with complex traits. We tested a set of highly constrained SNPs (hcSNPs) distributed genome-wide among ultra- or nearly-ultraconserved elements for association with 7 traits related to reproductive (age at natural menopause, number of children, age at first child, age at last child) and overall (longevity, BMI, and height) fitness. Using up to 24,047 European-American samples from the NHLBI Candidate Gene Association Resource, we observed an excess of associations with BMI and height. In an independent replication panel the most strongly associated SNPs showed an 8.4 fold enrichment of associations at the nominal level, including three variants in previously identified loci and one in a locus (DENND1A) previously shown to be associated with polycystic ovary syndrome. Finally, using 1,430 family trios, we showed that the transmission from heterozygous parents to offspring of the derived alleles of rare (frequency = 0.5%) hcSNPs are not biased, particularly after adjusting for the rates of genotype missingness and error in the data. The lack of transmission bias ruled out an immediately and strongly deleterious effect due to the rare derived alleles, consistent with the observation that mice homozygous for the deletion of ultraconserved elements showed no overt phenotype. Our study also illustrated the importance to carefully model potential technical confounders when analyzing genotype data of rare variants. The connecdenn family, Rab35 guanine nucleotide exchange factors interfacing with the clathrin machinery. Marat AL et al. Rabs constitute the largest family of monomeric GTPases, yet for the majority of Rabs relatively little is known about their activation and recruitment to vesicle-trafficking pathways. We recently identified connecdenn (DENND1A), which contains an N-terminal DENN (differentially expressed in neoplastic versus normal cells) domain, a common and evolutionarily ancient protein module. Through its DENN domain, connecdenn functions enzymatically as a guanine-nucleotide exchange factor (GEF) for Rab35. Here we identify two additional connecdenn family members and demonstrate that all connecdenns function as Rab35 GEFs, albeit with different levels of activity. The DENN domain of connecdenn 1 and 2 binds Rab35, whereas connecdenn 3 does not, indicating that Rab35 binding and activation are separable functions. Through their highly divergent C termini, each of the connecdenns binds to clathrin and to the clathrin adaptor AP-2. Interestingly, all three connecdenns use different mechanisms to bind AP-2. Characterization of connecdenn 2 reveals binding to the beta2-ear of AP-2 on a site that overlaps with that used by the autosomal recessive hypercholesterolemia protein and betaarrestin, although the sequence used by connecdenn 2 is unique. Loss of connecdenn 2 function through small interference RNA knockdown results in an enlargement of early endosomes, similar to what is observed upon loss of Rab35 activity. Our studies reveal connecdenn DENN domains as generalized GEFs for Rab35 and identify a new AP-2-binding motif, demonstrating a complex link between the clathrin machinery and Rab35 activation.

Cellular localization

Cytoplasmic, Nuclear

Comment

GWAS123

Ovarian function

Steroid metabolism

Comment

Overexpression of a DENND1A isoform produces a polycystic ovary syndrome theca phenotype. McAllister JM 2014 et al. Polycystic ovary syndrome (PCOS), characterized by increased ovarian androgen biosynthesis, anovulation, and infertility, affects 5-7% of reproductive-age women. Genome-wide association studies identified PCOS candidate loci that were replicated in subsequent reports, including DENND1A, which encodes a protein associated with clathrin-coated pits where cell-surface receptors reside. However, these studies provided no information about functional roles for DENND1A in the pathogenesis of PCOS. DENND1A protein was located in the cytoplasm as well as nuclei of theca cells, suggesting a possible role in gene regulation. DENND1A immunostaining was more intense in the theca of PCOS ovaries. Using theca cells isolated and propagated from normal cycling and PCOS women, we found that DENND1A variant 2 (DENND1A.V2) protein and mRNA levels are increased in PCOS theca cells. Exosomal DENND1A.V2 RNA was significantly elevated in urine from PCOS women compared with normal cycling women. Forced overexpression of DENND1A.V2 in normal theca cells resulted in a PCOS phenotype of augmented CYP17A1 and CYP11A1 gene transcription, mRNA abundance, and androgen biosynthesis. Knock-down of DENND1A.V2 in PCOS theca cells reduced androgen biosynthesis and CYP17A1 and CYP11A1 gene transcription. An IgG specific to DENND1A.V2 also reduced androgen biosynthesis and CYP17 and CYP11A1 mRNA when added to the medium of cultured PCOS theca cells. We conclude that the PCOS candidate gene, DENND1A, plays a key role in the hyperandrogenemia associated with PCOS. These observations have both diagnostic and therapeutic implications for this common disorder. /////////////////////////

Expression regulated by

mir130b

Comment

MicroRNA Profiling Reveals miRNA-130b-3p Mediates DENND1A Variant 2 Expression and Androgen Biosynthesis. McAllister JM et al. (2019) Polycystic ovary syndrome (PCOS) is a common endocrine disorder of reproductive aged women involving overproduction of ovarian androgens, and in some cases from the adrenal cortex. Family studies have established that PCOS is a complex heritable disorder with genetic and epigenetic components. Several small, non-coding RNAs (microRNAs) have been shown to be differentially expressed in ovarian cells, follicular fluid, and in the circulation of women with PCOS. However, there are no reports of global microRNA expression and target gene analyses in ovarian theca cells isolated from normal cycling and PCOS women, which are key to elucidating the basis for the hyperandrogenemia characteristic of PCOS. Using small RNA deep-sequencing, we identified 18 differentially expressed microRNAs in PCOS theca cells, of these, miR-130b-3p was predicted to target one of the PCOS GWAS candidates, DENND1A. We previously reported that DENND1A.V2, a truncated isoform of DENND1A, is upregulated in PCOS theca cells and mediates augmented androgen biosynthesis in PCOS theca cells. Comparison of miR-130b-3p in normal and PCOS theca cells demonstrated decreased miR-130b-3p expression in PCOS theca cells, which was correlated with increased DENND1A.V2, CYP17A1 mRNA and androgen biosynthesis. miR-130b-3p mimic studies established that decreased miR130b-3p is correlated with increased DENND1A.V2 and CYP17A1 expression. Thus, in addition to genetic factors, post-translational regulatory mechanisms via miR-130b-3p underly androgen excess in PCOS. IPA Pathway and Network Analyses suggests a network by which of miR-130b-3p, DENND1A, the LHCGR, RAB5B and the signaling pathways they potentially target may mediate increased hyperandrogenism is PCOS.//////////////////

Ovarian localization

Theca

Comment

candidate123

Follicle stages

Comment

Phenotypes

PCO (polycystic ovarian syndrome)

Mutations

14 mutations

Species: human
Mutation name: None
type: naturally occurring
fertility: subfertile
Comment: Genome-wide association study identifies susceptibility loci for polycystic ovary syndrome on chromosome 2p16.3, 2p21 and 9q33.3. Chen ZJ et al. Polycystic ovary syndrome (PCOS) is a common metabolic disorder in women. To identify causative genes, we conducted a genome-wide association study (GWAS) of PCOS in Han Chinese. The discovery set included 744 PCOS cases and 895 controls; subsequent replications involved two independent cohorts (2,840 PCOS cases and 5,012 controls from northern Han Chinese; 498 cases and 780 controls from southern and central Han Chinese). We identified strong evidence of associations between PCOS and three loci: 2p16.3 (rs13405728; combined P-value by meta-analysis P(meta) = 7.55 ?10???, odds ratio (OR) 0.71); 2p21 (rs13429458, P(meta) = 1.73 ?10???, OR 0.67); and 9q33.3 (rs2479106, P(meta) = 8.12 ?10???, OR 1.34). These findings provide new insight into the pathogenesis of PCOS. Follow-up studies of the candidate genes in these regions are recommended. A region showing a significant association with PCOS is on chromosome 9q33.3. The six significant SNPs (1.42 ?10−13 ≤ Pmeta ≤ 8.12 ?10−19; Supplementary Table 1) were located within a 42.3-kb region in a LD block within DENND1A (Fig. 2c). Conditional logistic regression analysis showed two independent associations, which can be represented by rs10818854 and rs2479106, both within DENND1A.

Species: human
Mutation name: None
type: naturally occurring
fertility: subfertile
Comment: Replication of association of DENND1A and THADA variants with polycystic ovary syndrome in European cohorts. Goodarzi MO et al. BackgroundPolycystic ovary syndrome (PCOS) is a complex endocrine disorder with a strong familial component. PCOS is characterised by hyperandrogenaemia and irregular menses. A recent genome-wide association study (GWAS) of PCOS in a Chinese cohort identified three reproducible PCOS susceptibility loci mapping to 2p16.3 (luteinising hormone/choriogonadotropin receptor; LHCGR), 2p21 (thyroid associated protein; THADA), and 9q33.3 (DENN/MADD domain containing 1A; DENNDIA). The impact of these loci in non-Chinese PCOS cohorts remains to be determined.Methods and resultsThe study tested association with PCOS of seven single nucleotide polymorphisms mapping to the three Chinese PCOS loci in two European derived PCOS cohorts (cohort A = 939 cases and 957 controls; cohort B = 535 cases and 845 controls). Cases fulfilled the National Institute of Child Health & Human Development criteria for PCOS. Variation in DENND1A was strongly associated with PCOS in the study cohort (p(combined cohorts)=10(-8)); multiple variants in THADA were also associated with PCOS, while there was no significant evidence for association of LHCGR variation with PCOS. The present study had >80% power to detect an effect of similar size as was observed by Chen et al for DENND1A and THADA, but reduced power (at <40%) for LHCGR at p=0.0001. The study had sufficient power (57-88%) for LHCGR at p=0.01.ConclusionsAt least two of the PCOS susceptibility loci identified in the Chinese PCOS GWAS (DENND1A and THADA) are also associated with PCOS in European derived populations, and are therefore likely to be important in the aetiology of PCOS regardless of ethnicity. The analysis of the LHCGR gene was not sufficiently powered to detect modest effects.

Species: human
Mutation name: None
type: naturally occurring
fertility: subfertile
Comment: Variants in DENND1A Are Associated with Polycystic Ovary Syndrome in Women of European Ancestry. Welt CK et al. Context:A genome-wide association study has identified three loci (five independent signals) that confer risk for polycystic ovary syndrome (PCOS) in Han Chinese women. Replication is necessary to determine whether the same variants confer risk for PCOS in women of European ancestry.Objective:The objective of the study was to test whether these PCOS risk variants in Han Chinese women confer risk for PCOS in women of European ancestry.Design:This was a case-control study.Setting:The study was conducted at deCODE Genetics in Iceland and two academic medical centers in the United States.Patients:Cases were 376 Icelandic women and 565 and 203 women from Boston, MA, and Chicago, IL, respectively, all diagnosed with PCOS by the National Institutes of Health criteria. Controls were 16,947, 483, and 189 women not known to have PCOS from Iceland, Boston, and Chicago, respectively.Intervention:There were no interventions.Main Outcomes:Main outcomes were allele frequencies for seven variants in PCOS cases and controls.Results:Two strongly correlated Han Chinese PCOS risk variants on chromosome 9q33.3, rs10986105[C], and rs10818854[A], were replicated in samples of European ancestry with odds ratio of 1.68 (P = 0.00033) and odds ratio of 1.53 (P = 0.0019), respectively. Other risk variants at 2p16.3 (rs13405728), 2p21 (rs12468394, rs12478601, and rs13429458), and 9q33.3 (rs2479106), or variants correlated with them, did not associate with PCOS. The same allele of rs10986105 that increased the risk of PCOS also increased the risk of hyperandrogenism in women without PCOS from Iceland and demonstrated a stronger risk for PCOS defined by the National Institutes of Health criteria than the Rotterdam criteria.Conclusions:We replicated one of the five Chinese PCOS association signals, represented by rs10986105 and rs10818854 on 9q33, in individuals of European ancestry. Examination of the subjects meeting at least one of the Rotterdam criteria for PCOS suggests that the variant may be involved in the hyperandrogenism and possibly the irregular menses of PCOS.

Species: human
Mutation name: None
type: naturally occurring
fertility: subfertile
Comment: Genetic Alterations within the DENND1A Gene in Patients with Polycystic Ovary Syndrome (PCOS). Eriksen MB 2013 et al. Polycystic ovary syndrome (PCOS), the most common endocrine disease among premenopausal women, is caused by both genes and environment. We and others previously reported association between single nucleotide polymorphisms (SNPs) in the DENND1A gene and PCOS. We therefore sequenced the DENND1A gene in white patients with PCOS to identify possible alterations that may be implicated in the PCOS pathogenesis. Patients were referred with PCOS and/or hirsutism between 1998 and 2011 (n = 261). PCOS was diagnosed according to the Rotterdam criteria (n = 165). Sequence analysis was performed in 10 patients with PCOS. Additional patients (n = 251) and healthy female controls (n = 248) were included for SNP genotyping. Patients underwent clinical examination including Ferriman-Gallwey score (FG-score), biochemical analyses and transvaginal ultrasound. Mutation analysis was carried out by bidirectional sequencing. SNP genotyping was tested by allelic discrimination in real-time PCR in the additional patients and controls. Sequencing of the DENND1A gene identified eight SNPs; seven were not known to be associated with any diseases. One missense SNP was detected (rs189947178, A/C), potentially altering the structural conformation of the DENND1A protein. SNP genotyping of rs189947178 showed significantly more carriers among patients with PCOS and moderate hirsutism compared to controls. However, due to small sample size and lack of multiple regression analysis supporting an association between rs189947178 and FG-score or PCOS diagnosis, this could be a false positive finding. In conclusion, sequence analysis of the DENND1A gene of patients with PCOS did not identify alterations that alone could be responsible for the PCOS pathogenesis, but a missense SNP (rs189947178) was identified in one patient and significantly more carriers of rs189947178 were found among patients with PCOS and moderate hirsutism vs. controls. Additional studies with independent cohort are needed to confirm this due to the small sample size of this study. /////////////////////////

Species: human
Mutation name:
type: naturally occurring
fertility: subfertile
Comment: Association of polycystic ovary syndrome susceptibility single nucleotide polymorphism rs2479106 and PCOS in Caucasian patients with PCOS or hirsutism as referral diagnosis. Eriksen MB et al. CONTEXT: Polycystic ovary syndrome (PCOS) is the most common endocrine disease among premenopausal women. A recent study found association between three single nucleotide polymorphisms (SNPs) and PCOS in a cohort of Han Chinese women. OBJECTIVE: To investigate the association between rs13405728 (LHCGR gene), rs13429458 (THADA gene) and rs2479106 (DENND1A gene), PCOS, hirsutism and metabolic and hormonal parameters in a well characterized cohort of Caucasian patients of Danish descendant with PCOS or hirsutism. STUDY DESIGN: Patients underwent clinical examination, hormone analyses, oral glucose tolerance test and transvaginal ultrasound. Genetic variation was tested using allelic discrimination by real-time PCR. PATIENTS: 268 patients referred to The Department of Endocrinology, Odense University Hospital, Denmark with PCOS or hirsutism between 1997 and 2011. Two hundred and forty-eight healthy females were included as controls. RESULTS: Genotype distributions and allele frequencies of rs13405728, rs13429458, and rs2479106 were comparable in patients and controls. The rs2479106 G allele was associated with a decreased PCOS susceptibility. None of the SNPs were associated with hirsutism or increased metabolic parameters. CONCLUSIONS: The rs2479106 G allele was associated with decreased PCOS susceptibility, thus confirming previously reported findings of association between rs2479106 and PCOS. Metabolic and hormonal parameters were comparable between genotypes of rs13405728 and rs2479106.////Polycystic ovary syndrome susceptibility single nucleotide polymorphisms in women with a single PCOS clinical feature. Cui L et al. (2015) What is the direct genetic contribution of the polycystic ovary syndrome (PCOS) susceptibility single nucleotide polymorphisms (SNPs), identified by previous genome-wide association studies (GWAS) to the definitive clinical features of the syndrome? Each single PCOS clinical feature had a specific genetic association, and rs4385527 in the chromosome 9 open reading frame 3 (C9orf3) conferred a particular risk to the three defined PCOS clinical features in this study, which suggested its fundamental role in the etiology of PCOS. PCOS is a heterogeneous disorder characterized by anovulation (OA), hyperandrogenism (HA) and polycystic ovary morphology (PCOM). Two previous GWAS in China have identified 15 independent susceptibility SNPs related to PCOS (PCOS-SNPs). However, little is known about the candidate gene of each clinical feature. Case-control study. Three independent groups of women were recruited from 2010 to 2012: 746 subjects with OA only, 278 subjects with HA only and 536 subjects with PCOM only. A total of 1790 healthy women with none of the above pathological characteristics were also enrolled as control subjects during the same time period. All participants were women of reproductive age. Genotype and allelic frequencies of 15 PCOS-SNPs were determined in all subjects using direct sequencing and Sequenom Arrays. The allelic frequencies of each case group were compared with the controls. After adjustment for age and BMI, variants in luteinizing hormone/choriogonadotropin receptor (LHCGR) (rs13405728), C9orf3 (rs4385527) and insulin receptor gene (INSR) (rs2059807) were strongly associated with OA (Padjust < 0.01, <0.001 and <0.05, respectively); rs4385527 in C9orf3 was strongly associated with HA (Padjust< 0.001); variants in the thyroid adenoma associated gene (THADA) (rs13429458 and rs12478601), DENN/MADD domain containing 1A (DENND1A)(rs10818854), and C9orf3 (rs4385527) were significantly associated with PCOM (Padjust < 0.01, <0.001, <0.05 and <0.001, respectively). The sample size of some case groups was relatively small, which therefore limited the statistical power of the analysis to a certain extent. The present study indicates a potential common genetic basis of three PCOS clinical features. Other specific associated genes may play a synergistic role, leading to heterogeneous pathophysiological changes. Additionally, the increased frequency of PCOS-risk alleles in women with single PCOS clinical features suggests that these subjects have an elevated risk of developing the syndrome, although they cannot be currently diagnosed. This research was supported by the National Basic Research Program of China (973 Program) (2012CB944700, 2011CB944502), the National Key Technology Research and Development Program(2011BAI17B00), the National Natural Science Foundation of China (81430029, 81201441, 81490743, 31371453), the Scientific Research Foundation of Shandong Province of Outstanding Young Scientist (2012BSE27089) and the Fundamental Research Funds of Shandong University(2014GN025). There were no competing interests.//////////////////

Species: human
Mutation name:
type: naturally occurring
fertility: subfertile
Comment: Further investigation in europeans of susceptibility variants for polycystic ovary syndrome discovered in genome-wide association studies of chinese individuals. Brower MA et al. (2015) Two genome-wide association studies (GWAS) of polycystic ovary syndrome (PCOS) have identified 11 susceptibility loci in Chinese individuals. Some of the risk loci identified in Chinese cohorts, mostly from the first GWAS, have been replicated in Europeans. Replication of the loci from the second GWAS in European cohorts is necessary to determine whether the same variants confer risk for PCOS in multiple ethnicities. The objective of the study was to determine the effects of the Chinese GWAS loci in European-origin individuals. This was a genetic association study. The study was conducted at a tertiary care academic center. Eight hundred forty-five European subjects with PCOS and 845 controls participated in the study. INTERVENTIONS included blood sampling and genotyping. The association between PCOS and 12 independent single-nucleotide polymorphisms mapping to seven of the Chinese GWAS loci in a European cohort was measured. Variants in DENND1A (P = .0002), THADA (P = .035), FSHR (P = .007), and INSR (P = .046) were associated with PCOS in Europeans. The genetic risk score, generated for each subject based on the total number of risk alleles, was associated with the diagnosis of PCOS (P < .0001) and remained associated (P = .02), even after exclusion of the four variants individually associated with PCOS. At least four of the PCOS susceptibility loci identified in the Chinese GWAS are associated with PCOS in Europeans. The overall genetic burden for PCOS, as demonstrated by the risk score, is also associated with the diagnosis of PCOS in Europeans. The PCOS susceptibility loci identified in the Chinese GWAS are thus likely to play an important role in the etiology of PCOS across ethnicities.//////////////////

Species: human
Mutation name:
type: naturally occurring
fertility: subfertile
Comment: DENND1A gene variants in Bahraini Arab women with polycystic ovary syndrome. Gammoh E et al. (2015) Recent genome-wide association studies and replication analyses reported an association between variants of DENND1A gene and polycystic ovary syndrome (PCOS), mostly in Asians. We therefore examined whether the common DENND1A SNPs rs10818854, rs2479106, and rs10986105 are associated with PCOS in Bahraini Arab population. This case-control study involved 191 women with PCOS diagnosed according to the Rotterdam criteria, and 202 control women. SNP genotyping was performed by the allelic discrimination in real-time PCR. The outcome was that the minor allele frequencies of SNPs rs10818854, rs2479106, and rs10986105 were similar between women with PCOS and control women (P >0.05), even before correcting for multiple testing, and none of the tested DENND1A SNPs were associated with PCOS under co-dominant, dominant, or recessive genetic models. None of the tested DENND1A variants were associated with PCOS features (hirsutism, insulin sensitivity, menses pattern, free testosterone, and free androgen index). Taking common GTA haplotype as reference (OR=1.00), [rs10818854/rs2479106/rs10986105] 3-locus haplotype analysis demonstrated lack of association of any of the DENND1A haplotypes with PCOS, even before correcting for multiple testing. To conclude we demonstrated lack of association of DENND1A SNPs rs10818854, rs2479106, and rs10986105, previously associated with PCOS in Asians, with PCOS in Bahraini Arab women.//////////////////

Species: human
Mutation name:
type: naturally occurring
fertility: subfertile
Comment: The association of DENND1A gene polymorphisms and polycystic ovary syndrome risk: a systematic review and meta-analysis. Gao J et al. (2016) Polycystic ovary syndrome is heterogeneity disease, and the association with DEEND1A gene has been discussed incompatibly for a long time. We conducted a meta-analysis to evaluate the rs10818854, rs2479106, and rs10986105 polymorphism in DENND1A gene with PCOS susceptibility. Meta-analysis was performed for common allele versus rare allele using random effect model on published papers from January 1, 1980 to October 1, 2015. Subgroup analysis, sensitivity analysis and publication bias were also carried out ultimately. The combined odds ratio (OR) with 95 % confidence interval (95 % CI) was calculated to estimate the strength of the association. The results showed that rs10818854 (OR = 1.36, 95 % CI 1.12-1.61) and rs10986105 (OR = 1.39, 95 % CI 1.20-1.58) polymorphism increased the risk of PCOS probably. A significant association was also found between rs2479106 mutation and Asian PCOS patients but not Europeans (OR = 1.32, 95 % CI 1.25-1.39; OR = 1.01, 95 % CI 0.97-1.05, respectively). In conclusion, the DENND1A gene variant is likely to have influence on PCOS risk. Further studies are warranted to assess these associations in greater detail, especially in different populations and different subtype of PCOS patients.//////////////////

Species: mouse
Mutation name:
type: null mutation
fertility: embryonic lethal
Comment: Dennd1a, a susceptibility gene for polycystic ovary syndrome, is essential for mouse embryogenesis. Shi J et al. (2019) The DENND1A has been identified as a guanine nucleotide exchange factor (GEF) for small GTPase Rab35, which functions in endocytic trafficking to mediate the recycling of selective cargos. Genetic alterations within the DENND1A gene have been implicated in human disease such as polycystic ovary syndrome (PCOS). However, the role of DENND1A in developmental and reproductive processes is largely unknown. Using Dennd1a gene knockout mice, we uncovered that homogeneous Dennd1a-/- mutants died around embryonic day (E) 14.5. The brain of Dennd1a-/- embryos exhibited defects, partially attributed to the dysregulation of cell division and survival in the telencephalon. The transcription of Fgf8 mRNA was ectopically elevated in the dorsal midline of telencephalon, concomitant with a decrease of active β-catenin and Axin2 in the brain of Dennd1a-/- embryos. During liver morphogenesis, the ablation of Dennd1a impaired hepatic cell proliferation, the differentiation of hepatocyte, and hepatic hematopoiesis. In addition, loss of Dennd1a also affected the development of primordial germ cells (PGCs). We demonstrate that Dennd1a, a susceptibility gene for PCOS, is essential for embryogenesis, probably through the mediation of endocytic recycling of selective cargos that are involved in cell signaling crucial for the development of multiple embryonic organ systems. This article is protected by copyright. All rights reserved.//////////////////

Species: human
Mutation name:
type: naturally occurring
fertility: subfertile
Comment: Family-based quantitative trait meta-analysis implicates rare noncoding variants in DENND1A in polycystic ovary syndrome. Dapas M et al. (2019) Polycystic ovary syndrome (PCOS) is among the most common endocrine disorders of premenopausal women, affecting 5-15% of this population depending on the diagnostic criteria applied. It is characterized by hyperandrogenism, ovulatory dysfunction and polycystic ovarian morphology. PCOS is highly heritable, but only a small proportion of this heritability can be accounted for by the common genetic susceptibility variants identified to date. The objective of this study was to test whether rare genetic variants contribute to PCOS pathogenesis.Design, Patients, and Methods: We performed whole-genome sequencing on DNA from 261 individuals from 62 families with one or more daughters with PCOS. We tested for associations of rare variants with PCOS and its concomitant hormonal traits using a quantitative trait meta-analysis. We found rare variants in DENND1A (P=5.31×10-5, Padj=0.039) that were significantly associated with reproductive and metabolic traits in PCOS families. Common variants in DENND1A have previously been associated with PCOS diagnosis in genome-wide association studies. Subsequent studies indicated that DENND1A is an important regulator of human ovarian androgen biosynthesis. Our findings provide additional evidence that DENND1A plays a central role in PCOS and suggest that rare noncoding variants contribute to disease pathogenesis.//////////////////

Species: human
Mutation name:
type: naturally occurring
fertility: subfertile
Comment: Association analysis between the tag single nucleotide polymorphisms of DENND1A and the risk of polycystic ovary syndrome in Chinese Han women. Zhu YN et al. (2020) The DENND1A gene is one of the most important sites associated with polycystic ovary syndrome (PCOS). We attempted to analyze the correlation between five single nucleotide polymorphisms (SNPs) in the DENND1A gene and the development of PCOS. A total of 346 PCOS patients and 225 normal ovulatory women were involved in the case-control study. Clinical variables and hormones were recorded. According to the Hap Map database, five tagging SNPs (rs2479106, rs2768819, rs2670139, rs2536951 and rs2479102) in the DENND1A gene were identified. The TaqMan probe and the PCR-RFLP (restriction fragment length polymorphism) methods were used for revealing these genotypes. TaqMan Genotype Software was used to analyze the alleles of the five SNPs. Linkage disequilibrium and the gene frequency analysis demonstrated that the CCGGG haplotype might increase the risk of PCOS (P = 0.038, OR = 1.89, 95% CI = 1.027-3.481). Significant differences were found in genotypic and allelic distributions at the rs2536951 and rs2479102 loci between PCOS women and controls (P < 0.001). The LH levels and LH/FSH ratios were higher in PCOS patients than in the control group. A detailed analysis revealed that for the rs2479106 locus, these two values were significantly different in the control subjects who had AA, AG and GG genotypes (P = 0.013 and P = 0.007, respectively), and for the rs2468819 locus, these two values were significantly different among the PCOS patients with AA, AG and GG genotypes (P = 0.013 and 0.002, respectively). The tagging SNPs rs2479106 and rs2468819 in the DENND1A gene are associated with PCOS in the Chinese population, whereas rs2670139, rs2536951 and rs2479102 are not correlated with PCOS in the same population.//////////////////

Species: human
Mutation name:
type: None
fertility: None
Comment: DENND1A encodes a domain that can bind to ERAP1, whose serum level has been reported to be associated with polycystic ovary syndrome accompanied by obesity (DEL VILLAR and MILLER 2004; OLSZANECKA-GLINIANOWICZ et al. 2007).

Species: human
Mutation name:
type: naturally occurring
fertility: subfertile
Comment: Family-based quantitative trait meta-analysis implicates rare noncoding variants in DENND1A in polycystic ovary syndrome. Dapas M et al. (2020) Polycystic ovary syndrome (PCOS) is among the most common endocrine disorders of premenopausal women, affecting 5-15% of this population depending on the diagnostic criteria applied. It is characterized by hyperandrogenism, ovulatory dysfunction and polycystic ovarian morphology. PCOS is highly heritable, but only a small proportion of this heritability can be accounted for by the common genetic susceptibility variants identified to date. The objective of this study was to test whether rare genetic variants contribute to PCOS pathogenesis.Design, Patients, and Methods: We performed whole-genome sequencing on DNA from 261 individuals from 62 families with one or more daughters with PCOS. We tested for associations of rare variants with PCOS and its concomitant hormonal traits using a quantitative trait meta-analysis. We found rare variants in DENND1A (P=5.31×10-5, Padj=0.039) that were significantly associated with reproductive and metabolic traits in PCOS families. Common variants in DENND1A have previously been associated with PCOS diagnosis in genome-wide association studies. Subsequent studies indicated that DENND1A is an important regulator of human ovarian androgen biosynthesis. Our findings provide additional evidence that DENND1A plays a central role in PCOS and suggest that rare noncoding variants contribute to disease pathogenesis.//////////////////

Species: bovine
Mutation name:
type: naturally occurring
fertility: fertile
Comment: Genetic variations of bovine PCOS-related DENND1A gene identified in GWAS significantly affect female reproductive traits. Zheng J et al. (2021) Genome-wide association studies (GWAS) have identified DENND1A as a potential candidate gene linked to the fertility-related phenotypes in dairy cows. However, to date, no studies have examined the association of the DENND1A insertion/deletions (indels) to bovine fertility on a large scale. Herein, two indel sites, including P4-del-26-bp and P8-ins-15-bp were identified in 1064 Holstein cows. The values of the minor allelic frequency (MAF) ranged between 0.471 (deletion) and 0.230 (deletion), respectively, and combined four different haplotypes by analyzing the haplotype combination. It is noteworthy that P4-del-26-bp is associated with the ovarian width (P = 0.0004) and corpus luteum diameter (P = 0.004). Meanwhile, P8-ins-15-bp was found to have a significant association with the ovarian width (P = 0.020), ovarian weight (P = 0.004), the number of mature follicles (P = 0.020), and diameter of the mature follicles (P = 0.016). Furthermore, the combinatorial analysis showed that the two indel combined-genotypes were significantly related to several reproductive traits (ovarian width, ovarian weight, etc.). Collectively, our findings indicated that these two novel indels and their combinations are correlated with the reproductive traits, and hence, they can serve in the marker-assisted selection (MAS) in cattle breeding. Nevertheless, further functional experiments are needed for understanding the mechanisms of these indels in cattle reproduction in a better way.//////////////////

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