Inactivating<i>PAPSS2</i>Mutations in a Patient with Premature Pubarche

Noordam, C.; Dhir, Vivek; McNelis, Joanne; Schlereth, Florian; Hanley, Neil A.; Krone, Nils; Smeitink, Jan A.M.; Smeets, Roel; Sweep, Fred C.G.J.; Grinten, Hedi L Claahsen–van der; Arlt, Wiebke

doi:10.1056/nejmoa0810489

Cited by 145 publications

(150 citation statements)

References 27 publications

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“…Sequencing of the PAPSS2 gene in our patient revealed compound heterozygous mutations: a nonsense mutation, R329X, resulting in early truncation of the PAPSS2 ATP sulphurylase subdomain and a missense mutation, T48R, located in an area of the PAPSS2 APS kinase domain that is crucial for protein function. In vitro assays demonstrated complete disruption of DHEA sulphation by the R329X nonsense mutation while T48R maintained 5% residual activity (136). Interestingly, the mother of the patient, who carried R329X on one allele, developed symptoms of PCOS including obesity, oligomenorrhoea and hirsutism at the age of 30 years, suggestive of a possible impact of milder genetic variation in PAPSS2 on presentation with androgen excess.…”

Section: Acrd (Hexose-6-phosphate Deficiency)mentioning

confidence: 91%

“…The significance of relatively low HSD3B2 expression in the adrenal ZR that would consequently shift steroidogenesis towards DHEA is endorsed by earlier studies based on human adrenal primary cultures (126). Recent work has highlighted the significance of two further enzyme systems in the regulation of adrenal androgen synthesis, with associated inactivating mutations identified as novel monogenic causes of PA: apparent cortisone reductase deficiency (ACRD) (135) and apparent DHEA sulfotransferase deficiency (136).…”

Section: Adrenal Steroidogenesis During Adrenarchementioning

confidence: 99%

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Premature adrenarche: novel lessons from early onset androgen excess

Idkowiak

Lavery

Dhir

et al. 2011

European Journal of Endocrinology

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110

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Adrenarche reflects the maturation of the adrenal zona reticularis resulting in increased secretion of the adrenal androgen precursor DHEA and its sulphate ester DHEAS. Premature adrenarche (PA) is defined by increased levels of DHEA and DHEAS before the age of 8 years in girls and 9 years in boys and the concurrent presence of signs of androgen action including adult-type body odour, oily skin and hair and pubic hair growth. PA is distinct from precocious puberty, which manifests with the development of secondary sexual characteristics including testicular growth and breast development. Idiopathic PA (IPA) has long been considered an extreme of normal variation, but emerging evidence links IPA to an increased risk of developing the metabolic syndrome (MS) and thus ultimately cardiovascular morbidity. Areas of controversy include the question whether IPA in girls is associated with a higher rate of progression to the polycystic ovary syndrome (PCOS) and whether low birth weight increases the risk of developing IPA. The recent discoveries of two novel monogenic causes of early onset androgen excess, apparent cortisone reductase deficiency and apparent DHEA sulphotransferase deficiency, support the notion that PA may represent a forerunner condition for PCOS. Future research including carefully designed longitudinal studies is required to address the apparent link between early onset androgen excess and the development of insulin resistance and the MS.

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Section: Acrd (Hexose-6-phosphate Deficiency)mentioning

confidence: 91%

Section: Adrenal Steroidogenesis During Adrenarchementioning

confidence: 99%

Premature adrenarche: novel lessons from early onset androgen excess

Idkowiak

Lavery

Dhir

et al. 2011

European Journal of Endocrinology

Self Cite

110

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“…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

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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.

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“…Highly sulphonated glycoproteins, including heparan sulphate proteoglycans (HSPGs), are critical for maintaining developmental cell signalling pathways in Drosophila and Caenorhabditis elegans (Sen et al 1998, Lin et al 1999, Dejima et al 2006) and contribute to tissue remodelling of the reproductive tract during gestation (Yanagishita 1994) and fetal kidney and brain development (Bullock et al 1998, Yamaguchi 2001. The importance of HSPG sulphonation in mammalian gestation is highlighted by the phenotypes of heparan sulphotransferase knockout (Hs3t1 K/K ) mice, which exhibit reduced fecundity due (2003,2004,2005,2006,2008,2009,2011) and Lee et al (2006Lee et al ( , 2007 2009). Importantly, sulphonation of CSPGs in chondrocytes is essential for normal skeletal growth and development, and several chrondrodysplasias have been attributed to genetic defects that lead to decreased CSPG sulphonation capacity (Table 1).…”

Section: Argü Eso and Gipson 2006 Dawson Et Al 2009)mentioning

confidence: 99%

Role of sulphate in development

Dawson¹

2013

Reproduction

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Sulphate contributes to numerous processes in mammalian physiology, particularly during development. Sulphotransferases mediate the sulphate conjugation (sulphonation) of numerous compounds, including steroids, glycosaminoglycans, proteins, neurotransmitters and xenobiotics, transforming their biological activities. Importantly, the ratio of sulphonated to unconjugated molecules plays a significant physiological role in many of the molecular events that regulate mammalian growth and development. In humans, the fetus is unable to generate its own sulphate and therefore relies on sulphate being supplied from maternal circulation via the placenta. To meet the gestational needs of the growing fetus, maternal blood sulphate concentrations double from mid-gestation. Maternal hyposulphataemia has been linked to fetal sulphate deficiency and late gestational fetal loss in mice. Disorders of sulphonation have also been linked to a number of developmental disorders in humans, including skeletal dysplasias and premature adrenarche. While recognised as an important nutrient in mammalian physiology, sulphate is largely unappreciated in clinical settings. In part, this may be due to technical challenges in measuring sulphate with standard pathology equipment and hence the limited findings of perturbed sulphate homoeostasis affecting human health. This review article is aimed at highlighting the importance of sulphate in mammalian development, with basic science research being translated through animal models and linkage to human disorders.Reproduction (2013) 146 R81-R89

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InactivatingPAPSS2Mutations in a Patient with Premature Pubarche

Cited by 145 publications

References 27 publications

Premature adrenarche: novel lessons from early onset androgen excess

Premature adrenarche: novel lessons from early onset androgen excess

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

Role of sulphate in development

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