A GWAS including 192,986 European and 1636 Asian participants identifies 50 novel discrete associ... more A GWAS including 192,986 European and 1636 Asian participants identifies 50 novel discrete associations with eye color.
Can high resolution array-CGH analysis on a cohort of women showing a primary ovarian insufficien... more Can high resolution array-CGH analysis on a cohort of women showing a primary ovarian insufficiency (POI) phenotype in young age identify copy number variants (CNVs) with a deleterious effect on ovarian function? SUMMARY ANSWER: This approach has proved effective to clarify the role of CNVs in POI pathogenesis and to better unveil both novel candidate genes and pathogenic mechanisms. WHAT IS KNOWN ALREADY: POI describes the progression toward the cessation of ovarian function before the age of 40 years. Genetic causes are highly heterogeneous and despite several genes being associated with ovarian failure, most of genetic basis of POI still needs to be elucidated.
We carried out a trans-ancestry genome-wide association and replication study of blood pressure p... more We carried out a trans-ancestry genome-wide association and replication study of blood pressure phenotypes among up to 320,251 individuals of East Asian, European and South Asian ancestry. We find genetic variants at 12 new loci to be associated with blood pressure (P = 3.9 × 10(-11) to 5.0 × 10(-21)). The sentinel blood pressure SNPs are enriched for association with DNA methylation at multiple nearby CpG sites, suggesting that, at some of the loci identified, DNA methylation may lie on the regulatory pathway linking sequence variation to blood pressure. The sentinel SNPs at the 12 new loci point to genes involved in vascular smooth muscle (IGFBP3, KCNK3, PDE3A and PRDM6) and renal (ARHGAP24, OSR1, SLC22A7 and TBX2) function. The new and known genetic variants predict increased left ventricular mass, circulating levels of NT-proBNP, and cardiovascular and all-cause mortality (P = 0.04 to 8.6 × 10(-6)). Our results provide new evidence for the role of DNA methylation in blood pressu...
Normal thyroid function is essential for health, but its genetic architecture remains poorly unde... more Normal thyroid function is essential for health, but its genetic architecture remains poorly understood. Here, for the heritable thyroid traits thyrotropin (TSH) and free thyroxine (FT4), we analyse whole-genome sequence data from the UK10K project (N=2,287). Using additional whole-genome sequence and deeply imputed data sets, we report meta-analysis results for common variants (MAF≥1%) associated with TSH and FT4 (N=16,335). For TSH, we identify a novel variant in SYN2 (MAF=23.5%, P=6.15 × 10(-9)) and a new independent variant in PDE8B (MAF=10.4%, P=5.94 × 10(-14)). For FT4, we report a low-frequency variant near B4GALT6/SLC25A52 (MAF=3.2%, P=1.27 × 10(-9)) tagging a rare TTR variant (MAF=0.4%, P=2.14 × 10(-11)). All common variants explain ≥20% of the variance in TSH and FT4. Analysis of rare variants…
Variation in body iron is associated with or causes diseases, including anaemia and iron overload... more Variation in body iron is associated with or causes diseases, including anaemia and iron overload. Here, we analyse genetic association data on biochemical markers of iron status from 11 European-population studies, with replication in eight additional cohorts (total up to 48,972 subjects). We find 11 genome-wide-significant…
Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiova... more Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largel...
Early menopause (EM) affects up to 10% of the female population, reducing reproductive lifespan c... more Early menopause (EM) affects up to 10% of the female population, reducing reproductive lifespan considerably. Currently, it constitutes the leading cause of infertility in the western world, affecting mainly those women who postpone their first pregnancy beyond the age of 30 years. The genetic aetiology of EM is largely unknown in the majority of cases. We have undertaken a meta-analysis of genome-wide association studies (GWASs) in 3493 EM cases and 13 598 controls from 10 independent studies. No novel genetic variants were discovered, but the 17 variants previously associated with normal age at natural menopause as a quantitative trait (QT) were also associated with EM and primary ovarian insufficiency (POI). Thus, EM has a genetic aetiology which overlaps variation in normal age at menopause and is at least partly explained by the additive effects of the same polygenic variants. The combined effect of the common variants captured by the single nucleotide polymorphism arrays was estimated to account for ∼30% of the variance in EM. The association between the combined 17 variants and the risk of EM was greater than the best validated non-genetic risk factor, smoking.
The male-to-female sex ratio at birth is constant across world populations with an average of 1.0... more The male-to-female sex ratio at birth is constant across world populations with an average of 1.06 (106 male to 100 female live births) for populations of European descent. The sex ratio is considered to be affected by numerous biological and environmental factors and to have a heritable component. The aim of this study was to investigate the presence of common allele modest effects at autosomal and chromosome X variants that could explain the observed sex ratio at birth. We conducted a large-scale genome-wide association scan (GWAS) meta-analysis across 51 studies, comprising overall 114 863 individuals (61 094 women and 53 769 men) of European ancestry and 2 623 828 common (minor allele frequency >0.05) single-nucleotide polymorphisms (SNPs). Allele frequencies were compared between men and women for directly-typed and imputed variants within each study. Forward-time simulations for unlinked, neutral, autosomal, common loci were performed under the demographic model for European populations with a fixed sex ratio and a random mating scheme to assess the probability of detecting significant allele frequency differences. We do not detect any genomewide significant (P < 5 3 10 28) common SNP differences between men and women in this well-powered meta-analysis. The simulated data provided results entirely consistent with these findings. This large-scale investigation across ∼115 000 individuals shows no detectable contribution from common genetic variants to the observed skew in the sex ratio. The absence of sex-specific differences is useful in guiding genetic association study design, for example when using mixed controls for sex-biased traits.
We have previously reported that expression of the G6PD locus is correlated with the methylation ... more We have previously reported that expression of the G6PD locus is correlated with the methylation status of two islands of CpG dinucleotides which are 3' to the locus and in the 5' region of two adjacent genes of unknown function, P3 and GdX. We have now examined the methylation of a third CpG island in the promoter region of the G6PD gene itself in DNA from males, females and reactivants that express G6PD on the inactive X chromosome. Our results show that expression of the G6PD gene is associated with concordant demethylation of all three CpG islands in this 100-kb region of DNA.
We report the isolation and analysis of human genomic DNA clones spanning about 100 kb of the X c... more We report the isolation and analysis of human genomic DNA clones spanning about 100 kb of the X chromosome and comprising the entire gene coding for the enzyme glucose 6-phosphate dehydrogenase (G6PD). The G6PD gene is 18 kb long and consists of 13 exons: the protein-coding region is divided into 12 segments ranging in size from 12 to 236 bp; an intron is present in the 5' untranslated region. Mature G6PD mRNA has a single polyadeniylation site in HeLa cells. The major 5' end of mature G6PD mRNA in several cell lines is located 177 bp upstream of the translation initiating codon; longer mRNA molecules extending further in the 5' direction could be identified by Si mapping and by comparing genomic and cDNA sequences. The DNA sequence around the major mRNA start is very GC rich; as to putative transcription regulatory sequences, a non-canonical TATA box and 9 CCGCCC elements are present, but no CAAT element could be identified. The genomic DNA we have isolated includes another ubiquitously transcribed region, provisionally named the GdX gene. Although the function of GdX is as yet unknown, we have established that this gene is located about 40 kb downstream of G6PD and is transcribed in the same direction. A comparative analysis of the promoter region of G6PD and 10 other housekeeping enzyme genes has confmned the presence of a number of common features. In particular, in the eight cases in which a 'TATA' box is present, a conserved sequence of 25 bp is seen immediately downstream.
Glucose-6-phosphate dehydrogenase (G6PD) is a household enzyme that accounts, in many cells, for ... more Glucose-6-phosphate dehydrogenase (G6PD) is a household enzyme that accounts, in many cells, for about 0.03% of cellular protein. We have developed an assay for G6PD-specific mRNA based on in vitro translation of RNA from human fibroblasts and immunoprecipitation of the translation products with an anti-G6PD antiserum. By making use of this assay, G6PD mRNA has been purified 50 to 100-fold in three steps. We estimate that the mRNA encoding G6PD constitutes less than 0.02% of total poly(A)+ RNA in human fibroblasts. The size of the G6PD mRNA has been established in denaturing conditions as being in the range between 2800 and 3200 nucleotides. This has been confirmed by Northern blot analysis. Since the G6PD coding sequence is estimated to be about 1491 nucleotides, the G6PD mRNA has long untranslated sequences, most of which is at the 3' end and which may be heterogeneous in length. The sequence of the last 608 nucleotides of this mRNA has been determined.
The human X-linked gene encoding glucose 6-phosphate dehydrogenase (G6PD) is highly polymorphic; ... more The human X-linked gene encoding glucose 6-phosphate dehydrogenase (G6PD) is highly polymorphic; more than 300 G6PD variants have been identified. G6PD deficiency in different geographical areas appears to have arisen through independent mutational events, but within the same population it may also be heterogeneous. One example is the island of Sardinia, where careful clinical and biochemical studies have identified four different G6PD variants. We cloned and sequenced the four G6PD variants from Sardinia and found that only two mutations are responsible for G6PD deficiency in this area: one mutation is the cause of the G6PD Seattle-like phenotype, a milder form of G6PD deficiency; the other mutation is responsible for all forms of very severe G6PD deficiency in Sardinia and, possibly, in the Mediterranean.
The genetic polymorphism of an approximately 100-kb DNA region comprising and flanking the glucos... more The genetic polymorphism of an approximately 100-kb DNA region comprising and flanking the glucose-6-phosphate dehydrogenase (G6PD) gene on human chromosome Xq28 has been analyzed in detail. By using 14 unique sequence probes and 18 restriction enzymes, we have characterized 257 restriction fragments or 370 restriction sites. On testing 12-57 individual X chromosomes, all sites but one were nonpolymorphic. However, a PstI site that maps to exon 10 of the G6PD gene, which is still monomorphic in all British and Italian subjects tested, is polymorphic in west-African people. Specifically, it is absent from 22% of Nigerian X chromosomes. By sequence analysis we have shown that the absence of this PstI site results from a G----A replacement at position 1116, corresponding to the third base of a glutamine codon; no amino acid change is produced in the protein. Thus, a polymorphic silent mutation is demonstrated in a human gene.
We have investigated the process leading to differentiation of PC12 cells. This process is known ... more We have investigated the process leading to differentiation of PC12 cells. This process is known to include extension of neurites and changes in the expression of subsets of proteins involved in cytoskeletal rearrangements or in neurosecretion. To this aim, we have studied a PC12 clone (trk-PC12) stably transfected with the nerve growth factor receptor TrkA. These cells are able to undergo both spontaneous and neurotrophin-induced morphological differentiation. However, both undifferentiated and nerve growth factor-differentiated trk-PC12 cells appear to be completely defective in the expression of proteins of the secretory apparatus, including proteins of synaptic vesicles and large dense-core granules, neurotransmitter transporters, and neurotransmitter-synthesizing enzymes. These results indicate that neurite extension can occur independently of the presence of the neurosecretory machinery, including the proteins that constitute the fusion machine, suggesting the existence of dif...
His research areas are the physiology of ovarian function and its pharmacological manipulation. I... more His research areas are the physiology of ovarian function and its pharmacological manipulation. In recent years, his research has been focused on anti-Müllerian hormone and ovarian reserve.
Primary ovarian insufficiency (POI) is a critical fertility defect characterized by an anticipate... more Primary ovarian insufficiency (POI) is a critical fertility defect characterized by an anticipated and silent impairment of the follicular reserve, but its pathogenesis is largely unexplained. The frequent maternal inheritance of POI together with a remarkable dependence of ovarian folliculogenesis upon mitochondrial biogenesis and bioenergetics suggested the possible involvement of a generalized mitochondrial defect. Here, we verified the existence of a significant correlation between blood and ovarian mitochondrial DNA (mtDNA) content in a group of women undergoing ovarian hyperstimulation (OH), and then aimed to verify whether mtDNA content was significantly altered in the blood cells of POI women. We recruited 101 women with an impaired ovarian reserve: 59 women with premature ovarian failure (POF) and 42 poor responders (PR) to OH. A Taqman copy number assay revealed a significant mtDNA depletion (P,0.001) in both POF and PR women in comparison with 43 women of similar age and intact ovarian reserve, or 53 very old women with a previous physiological menopause. No pathogenic variations in the mitochondrial DNA polymerase c (POLG) gene were detected in 57 POF or PR women with low blood mtDNA content. In conclusion, blood cell mtDNA depletion is a frequent finding among women with premature ovarian aging, suggesting that a still undetermined but generalized mitochondrial defect may frequently predispose to POI which could then be considered a form of anticipated aging in which the ovarian defect may represent the first manifestation. The determination of mtDNA content in blood may become an useful tool for the POI risk prediction.
A GWAS including 192,986 European and 1636 Asian participants identifies 50 novel discrete associ... more A GWAS including 192,986 European and 1636 Asian participants identifies 50 novel discrete associations with eye color.
Can high resolution array-CGH analysis on a cohort of women showing a primary ovarian insufficien... more Can high resolution array-CGH analysis on a cohort of women showing a primary ovarian insufficiency (POI) phenotype in young age identify copy number variants (CNVs) with a deleterious effect on ovarian function? SUMMARY ANSWER: This approach has proved effective to clarify the role of CNVs in POI pathogenesis and to better unveil both novel candidate genes and pathogenic mechanisms. WHAT IS KNOWN ALREADY: POI describes the progression toward the cessation of ovarian function before the age of 40 years. Genetic causes are highly heterogeneous and despite several genes being associated with ovarian failure, most of genetic basis of POI still needs to be elucidated.
We carried out a trans-ancestry genome-wide association and replication study of blood pressure p... more We carried out a trans-ancestry genome-wide association and replication study of blood pressure phenotypes among up to 320,251 individuals of East Asian, European and South Asian ancestry. We find genetic variants at 12 new loci to be associated with blood pressure (P = 3.9 × 10(-11) to 5.0 × 10(-21)). The sentinel blood pressure SNPs are enriched for association with DNA methylation at multiple nearby CpG sites, suggesting that, at some of the loci identified, DNA methylation may lie on the regulatory pathway linking sequence variation to blood pressure. The sentinel SNPs at the 12 new loci point to genes involved in vascular smooth muscle (IGFBP3, KCNK3, PDE3A and PRDM6) and renal (ARHGAP24, OSR1, SLC22A7 and TBX2) function. The new and known genetic variants predict increased left ventricular mass, circulating levels of NT-proBNP, and cardiovascular and all-cause mortality (P = 0.04 to 8.6 × 10(-6)). Our results provide new evidence for the role of DNA methylation in blood pressu...
Normal thyroid function is essential for health, but its genetic architecture remains poorly unde... more Normal thyroid function is essential for health, but its genetic architecture remains poorly understood. Here, for the heritable thyroid traits thyrotropin (TSH) and free thyroxine (FT4), we analyse whole-genome sequence data from the UK10K project (N=2,287). Using additional whole-genome sequence and deeply imputed data sets, we report meta-analysis results for common variants (MAF≥1%) associated with TSH and FT4 (N=16,335). For TSH, we identify a novel variant in SYN2 (MAF=23.5%, P=6.15 × 10(-9)) and a new independent variant in PDE8B (MAF=10.4%, P=5.94 × 10(-14)). For FT4, we report a low-frequency variant near B4GALT6/SLC25A52 (MAF=3.2%, P=1.27 × 10(-9)) tagging a rare TTR variant (MAF=0.4%, P=2.14 × 10(-11)). All common variants explain ≥20% of the variance in TSH and FT4. Analysis of rare variants…
Variation in body iron is associated with or causes diseases, including anaemia and iron overload... more Variation in body iron is associated with or causes diseases, including anaemia and iron overload. Here, we analyse genetic association data on biochemical markers of iron status from 11 European-population studies, with replication in eight additional cohorts (total up to 48,972 subjects). We find 11 genome-wide-significant…
Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiova... more Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largel...
Early menopause (EM) affects up to 10% of the female population, reducing reproductive lifespan c... more Early menopause (EM) affects up to 10% of the female population, reducing reproductive lifespan considerably. Currently, it constitutes the leading cause of infertility in the western world, affecting mainly those women who postpone their first pregnancy beyond the age of 30 years. The genetic aetiology of EM is largely unknown in the majority of cases. We have undertaken a meta-analysis of genome-wide association studies (GWASs) in 3493 EM cases and 13 598 controls from 10 independent studies. No novel genetic variants were discovered, but the 17 variants previously associated with normal age at natural menopause as a quantitative trait (QT) were also associated with EM and primary ovarian insufficiency (POI). Thus, EM has a genetic aetiology which overlaps variation in normal age at menopause and is at least partly explained by the additive effects of the same polygenic variants. The combined effect of the common variants captured by the single nucleotide polymorphism arrays was estimated to account for ∼30% of the variance in EM. The association between the combined 17 variants and the risk of EM was greater than the best validated non-genetic risk factor, smoking.
The male-to-female sex ratio at birth is constant across world populations with an average of 1.0... more The male-to-female sex ratio at birth is constant across world populations with an average of 1.06 (106 male to 100 female live births) for populations of European descent. The sex ratio is considered to be affected by numerous biological and environmental factors and to have a heritable component. The aim of this study was to investigate the presence of common allele modest effects at autosomal and chromosome X variants that could explain the observed sex ratio at birth. We conducted a large-scale genome-wide association scan (GWAS) meta-analysis across 51 studies, comprising overall 114 863 individuals (61 094 women and 53 769 men) of European ancestry and 2 623 828 common (minor allele frequency >0.05) single-nucleotide polymorphisms (SNPs). Allele frequencies were compared between men and women for directly-typed and imputed variants within each study. Forward-time simulations for unlinked, neutral, autosomal, common loci were performed under the demographic model for European populations with a fixed sex ratio and a random mating scheme to assess the probability of detecting significant allele frequency differences. We do not detect any genomewide significant (P < 5 3 10 28) common SNP differences between men and women in this well-powered meta-analysis. The simulated data provided results entirely consistent with these findings. This large-scale investigation across ∼115 000 individuals shows no detectable contribution from common genetic variants to the observed skew in the sex ratio. The absence of sex-specific differences is useful in guiding genetic association study design, for example when using mixed controls for sex-biased traits.
We have previously reported that expression of the G6PD locus is correlated with the methylation ... more We have previously reported that expression of the G6PD locus is correlated with the methylation status of two islands of CpG dinucleotides which are 3' to the locus and in the 5' region of two adjacent genes of unknown function, P3 and GdX. We have now examined the methylation of a third CpG island in the promoter region of the G6PD gene itself in DNA from males, females and reactivants that express G6PD on the inactive X chromosome. Our results show that expression of the G6PD gene is associated with concordant demethylation of all three CpG islands in this 100-kb region of DNA.
We report the isolation and analysis of human genomic DNA clones spanning about 100 kb of the X c... more We report the isolation and analysis of human genomic DNA clones spanning about 100 kb of the X chromosome and comprising the entire gene coding for the enzyme glucose 6-phosphate dehydrogenase (G6PD). The G6PD gene is 18 kb long and consists of 13 exons: the protein-coding region is divided into 12 segments ranging in size from 12 to 236 bp; an intron is present in the 5' untranslated region. Mature G6PD mRNA has a single polyadeniylation site in HeLa cells. The major 5' end of mature G6PD mRNA in several cell lines is located 177 bp upstream of the translation initiating codon; longer mRNA molecules extending further in the 5' direction could be identified by Si mapping and by comparing genomic and cDNA sequences. The DNA sequence around the major mRNA start is very GC rich; as to putative transcription regulatory sequences, a non-canonical TATA box and 9 CCGCCC elements are present, but no CAAT element could be identified. The genomic DNA we have isolated includes another ubiquitously transcribed region, provisionally named the GdX gene. Although the function of GdX is as yet unknown, we have established that this gene is located about 40 kb downstream of G6PD and is transcribed in the same direction. A comparative analysis of the promoter region of G6PD and 10 other housekeeping enzyme genes has confmned the presence of a number of common features. In particular, in the eight cases in which a 'TATA' box is present, a conserved sequence of 25 bp is seen immediately downstream.
Glucose-6-phosphate dehydrogenase (G6PD) is a household enzyme that accounts, in many cells, for ... more Glucose-6-phosphate dehydrogenase (G6PD) is a household enzyme that accounts, in many cells, for about 0.03% of cellular protein. We have developed an assay for G6PD-specific mRNA based on in vitro translation of RNA from human fibroblasts and immunoprecipitation of the translation products with an anti-G6PD antiserum. By making use of this assay, G6PD mRNA has been purified 50 to 100-fold in three steps. We estimate that the mRNA encoding G6PD constitutes less than 0.02% of total poly(A)+ RNA in human fibroblasts. The size of the G6PD mRNA has been established in denaturing conditions as being in the range between 2800 and 3200 nucleotides. This has been confirmed by Northern blot analysis. Since the G6PD coding sequence is estimated to be about 1491 nucleotides, the G6PD mRNA has long untranslated sequences, most of which is at the 3' end and which may be heterogeneous in length. The sequence of the last 608 nucleotides of this mRNA has been determined.
The human X-linked gene encoding glucose 6-phosphate dehydrogenase (G6PD) is highly polymorphic; ... more The human X-linked gene encoding glucose 6-phosphate dehydrogenase (G6PD) is highly polymorphic; more than 300 G6PD variants have been identified. G6PD deficiency in different geographical areas appears to have arisen through independent mutational events, but within the same population it may also be heterogeneous. One example is the island of Sardinia, where careful clinical and biochemical studies have identified four different G6PD variants. We cloned and sequenced the four G6PD variants from Sardinia and found that only two mutations are responsible for G6PD deficiency in this area: one mutation is the cause of the G6PD Seattle-like phenotype, a milder form of G6PD deficiency; the other mutation is responsible for all forms of very severe G6PD deficiency in Sardinia and, possibly, in the Mediterranean.
The genetic polymorphism of an approximately 100-kb DNA region comprising and flanking the glucos... more The genetic polymorphism of an approximately 100-kb DNA region comprising and flanking the glucose-6-phosphate dehydrogenase (G6PD) gene on human chromosome Xq28 has been analyzed in detail. By using 14 unique sequence probes and 18 restriction enzymes, we have characterized 257 restriction fragments or 370 restriction sites. On testing 12-57 individual X chromosomes, all sites but one were nonpolymorphic. However, a PstI site that maps to exon 10 of the G6PD gene, which is still monomorphic in all British and Italian subjects tested, is polymorphic in west-African people. Specifically, it is absent from 22% of Nigerian X chromosomes. By sequence analysis we have shown that the absence of this PstI site results from a G----A replacement at position 1116, corresponding to the third base of a glutamine codon; no amino acid change is produced in the protein. Thus, a polymorphic silent mutation is demonstrated in a human gene.
We have investigated the process leading to differentiation of PC12 cells. This process is known ... more We have investigated the process leading to differentiation of PC12 cells. This process is known to include extension of neurites and changes in the expression of subsets of proteins involved in cytoskeletal rearrangements or in neurosecretion. To this aim, we have studied a PC12 clone (trk-PC12) stably transfected with the nerve growth factor receptor TrkA. These cells are able to undergo both spontaneous and neurotrophin-induced morphological differentiation. However, both undifferentiated and nerve growth factor-differentiated trk-PC12 cells appear to be completely defective in the expression of proteins of the secretory apparatus, including proteins of synaptic vesicles and large dense-core granules, neurotransmitter transporters, and neurotransmitter-synthesizing enzymes. These results indicate that neurite extension can occur independently of the presence of the neurosecretory machinery, including the proteins that constitute the fusion machine, suggesting the existence of dif...
His research areas are the physiology of ovarian function and its pharmacological manipulation. I... more His research areas are the physiology of ovarian function and its pharmacological manipulation. In recent years, his research has been focused on anti-Müllerian hormone and ovarian reserve.
Primary ovarian insufficiency (POI) is a critical fertility defect characterized by an anticipate... more Primary ovarian insufficiency (POI) is a critical fertility defect characterized by an anticipated and silent impairment of the follicular reserve, but its pathogenesis is largely unexplained. The frequent maternal inheritance of POI together with a remarkable dependence of ovarian folliculogenesis upon mitochondrial biogenesis and bioenergetics suggested the possible involvement of a generalized mitochondrial defect. Here, we verified the existence of a significant correlation between blood and ovarian mitochondrial DNA (mtDNA) content in a group of women undergoing ovarian hyperstimulation (OH), and then aimed to verify whether mtDNA content was significantly altered in the blood cells of POI women. We recruited 101 women with an impaired ovarian reserve: 59 women with premature ovarian failure (POF) and 42 poor responders (PR) to OH. A Taqman copy number assay revealed a significant mtDNA depletion (P,0.001) in both POF and PR women in comparison with 43 women of similar age and intact ovarian reserve, or 53 very old women with a previous physiological menopause. No pathogenic variations in the mitochondrial DNA polymerase c (POLG) gene were detected in 57 POF or PR women with low blood mtDNA content. In conclusion, blood cell mtDNA depletion is a frequent finding among women with premature ovarian aging, suggesting that a still undetermined but generalized mitochondrial defect may frequently predispose to POI which could then be considered a form of anticipated aging in which the ovarian defect may represent the first manifestation. The determination of mtDNA content in blood may become an useful tool for the POI risk prediction.
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Papers by D. Toniolo