PAPSS2 Deficiency Causes Androgen Excess via Impaired DHEA Sulfation—In Vitro and in Vivo Studies in a Family Harboring Two Novel PAPSS2 Mutations

Oostdijk, Wilma; Idkowiak, Jan; Mueller, Jonathan Wolf; House, Philip J.; Taylor, Angela E.; O’Reilly, Michael; Hughes, Beverly; Vries, Martine C. de; Kant, Sarina G.; Santen, Gijs; Verkerk, Annemieke J.M.H.; Uitterlinden, André G.; Wit, Jan M.; Losekoot, Monique; Arlt, Wiebke

doi:10.1210/jc.2014-3556

Cited by 66 publications

(66 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…MTHFD2 is likely responsible for mitochondrial production of both NADH and NADPH in rapidly proliferating cells [41]. PAPSS2 gene plays an important role in modulating ovarian function and female fertility by control of the bioavailability of ovarian androgen [42]. Adrenodoxin, a versatile ferredoxin, is involved in steroid hormone biosynthesis and vitamin D and bile acid metabolism [43].…”

Section: Discussionmentioning

confidence: 99%

Changes in Ovary Transcriptome and Alternative splicing at estrus from Xiang pigs with Large and Small Litter Size

Zhang

Tang

Ran

et al. 2019

Preprint

View full text Add to dashboard Cite

29 30 2 1 2 Abstract 3 Background/Aims: Litter size is one of the most important reproductive traits in pig breeding, which is affected by 4 multiple genes and the environment. Ovaries are the most important reproductive organs and have a profound impact 5 on the reproduction efficiency. Therefore, genetic differences in the ovaries may contribute to the observed 6 differences in litter size. Although QTLs and candidate genes have been reported to affect the litter size in many pig 7 breeds, however, the findings cannot elucidate the marked differences of the reproductive traits between breeds. The 8 aim of present work is to elucidate the mechanisms of the differences for the reproductive traits and identify 9 candidate genes associated with litter size in Xiang pig breed. Methods: The changes in ovary transcriptome and 10 alternative splicing were investigated at estrus between Xiang pigs with large and small litter size by RNA-seq 11 technology. The RNA-seq results were confirmed by RT-qPCR method. Results: We detected 16,219 -16,285 expressed 12 genes and 12 types of alternative splicing (AS) events in Xiang pig samples. A total of 762 differentially expressed genes 13 were identified by XL (Xiang pig group with larger litter size) vs XS (Xiang pig group with small litter size) sample 14 comparisons. A total of 34 genes were upregulated and 728 genes were downregulated in XL ovary samples compared 15 with the XS samples. Alternative splicing (AS) rates in XL samples were slightly lower than that observed in XS samples. 16 Most of differentially expressed genes were differentially regulated on AS level. Eleven candidate genes were 17 potentially identified to be related to Xiang pig fecundity and litter size, which may be closely related to the gonad 18 development, oocyte maturation or embryo quality. Conclusion: The significant changes in the expression of the 19 protein-coding genes and the level of alternative splicing in estrus ovarian transcriptome between XL and XS groups 20 probably are the molecular mechanisms of phenotypic variation in litter size. 21 22

show abstract

Section: Discussionmentioning

confidence: 99%

Changes in Ovary Transcriptome and Alternative splicing at estrus from Xiang pigs with Large and Small Litter Size

Zhang

Tang

Ran

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…It is likely that this premature onset of joint degeneration is due to impaired proteoglycan sulfation. Inactivating mutations in PAPSS2 have also been linked to andrenocortical androgen excess and premature pubarche due to impaired dehydroepiandrosterone (DHEA) sulfation (24,25). DHEA sulfate is believed to be a critical hormone with a myriad of anti-aging effects (26).…”

Section: Discussionmentioning

confidence: 99%

Gene Expression Differences Between Offspring of Long-Lived Individuals and Controls in Candidate Longevity Regions: Evidence forPAPSS2as a Longevity Gene

Yerges‐Armstrong

Chai

O’Connell

et al. 2016

GERONA

View full text Add to dashboard Cite

Although there is compelling evidence for a genetic contribution to longevity, identification of specific genes that robustly associate with longevity has been a challenge. In order to identify longevity-enhancing genes, we measured differential gene expression between offspring of long-lived Amish (older than 90 years; cases, n = 128) and spouses of these offspring (controls, n = 121) and correlated differentially expressed transcripts with locations of longevity-associated variants detected in a prior genome-wide association study (GWAS) of survival to age 90. Expression of one of these transcripts, 3′-phosphoadenosine 5′-phosphosulfate synthase 2 (PAPSS2), was significantly higher in offspring versus controls (4 × 10 −4 ) and this association was replicated using quantitative real-time polymerase chain reaction. PAPSS2, a sulfation enzyme located on chromosome 10, is ~80 kb upstream of the PAPSS2 transcription start site. We found evidence of cis-expression for the originally reported GWAS SNP and PAPSS2. Monogenic conditions linked to PAPSS2 include andrenocortical androgen excess resulting in premature pubarche and skeletal dysplasias, both of which have premature aging features. In summary, these findings provide novel evidence for PAPSS2 as a longevity locus and illustrate the value of harnessing multiple "-omic" approaches to identify longevity candidates. Keywords: Longevity genetics-Gene expression-PAPSS2Life span is the result of a complicated interplay between genetic and environmental factors. Although much of the genetic research on aging has focused on predisposition of age-related diseases such as cardiovascular and Alzheimer's disease, compelling evidence from animal models and human studies supports the existence of genetic factors that enhance life span itself by influencing cellular aging (1-3).Studies of twins reared together and twins reared apart suggest that genetic factors explained ~30% of the variance in longevity (4,5), and heritability of life span in the Old Order Amish was previously estimated as ~25% (6). A stronger genetic influence on longevity has been reported for more extreme life-span phenotypes (eg, premature death or exceptional survival) than for life span in general (7,8). A study by Perls and colleagues demonstrated that the siblings of centenarians are 8-17 times more likely to survive to age 100 compared with other individuals from their birth cohorts (9). Ashkenazi parents of centenarians were approximately seven times more likely to live to age 90 (10), and the Leiden Longevity Study found that mortality rates in first-degree relatives of long-lived individuals were 30% lower compared with the general population (11). These studies support the concept that longevity is a familial trait likely to be inherited and demonstrate the potential utility of using family studies in identifying longevity assurance genes.

show abstract

“…Over recent years, a number of PAPSS2 mutations have been reported in patients with SEMD/brachyolmia, with only very limited data on endocrine function [137-139]. Steroid metabolome profiling following an oral DHEA challenge, performed in a family with 2 brothers affected by PAPSS2 deficiency, revealed that also the mother, a heterozygous carrier of a severe loss-of-function mutation, had impaired DHEA sulfation with clinical and biochemical evidence of androgen excess [140]. …”

Section: Monogenic Disorders Of Adrenal Steroidogenesismentioning

confidence: 99%

Monogenic Disorders of Adrenal Steroidogenesis

2018

Self Cite

View full text Add to dashboard Cite

Disorders of adrenal steroidogenesis comprise autosomal recessive conditions affecting steroidogenic enzymes of the adrenal cortex. Those are located within the 3 major branches of the steroidogenic machinery involved in the production of mineralocorticoids, glucocorticoids, and androgens. This mini review describes the principles of adrenal steroidogenesis, including the newly appreciated 11-oxygenated androgen pathway. This is followed by a description of pathophysiology, biochemistry, and clinical implications of steroidogenic disorders, including mutations affecting cholesterol import and steroid synthesis, the latter comprising both mutations affecting steroidogenic enzymes and co-factors required for efficient catalysis. A good understanding of adrenal steroidogenic pathways and their regulation is crucial as the basis for sound management of these disorders, which in the majority present in early childhood.

show abstract

PAPSS2 Deficiency Causes Androgen Excess via Impaired DHEA Sulfation—In Vitro and in Vivo Studies in a Family Harboring Two Novel PAPSS2 Mutations

Cited by 66 publications

References 27 publications

Changes in Ovary Transcriptome and Alternative splicing at estrus from Xiang pigs with Large and Small Litter Size

Changes in Ovary Transcriptome and Alternative splicing at estrus from Xiang pigs with Large and Small Litter Size

Gene Expression Differences Between Offspring of Long-Lived Individuals and Controls in Candidate Longevity Regions: Evidence forPAPSS2as a Longevity Gene

Monogenic Disorders of Adrenal Steroidogenesis

Contact Info

Product

Resources

About