An in-frame deletion at the polymerase active site of POLD1 causes a multisystem disorder with lipodystrophy

Weedon, Michael N.; Ellard, Sian; Prindle, Marc J.; Caswell, Richard; Allen, Hana Lango; Oram, Richard A.; Godbole, Koumudi; Yajnik, Chittaranjan S; Sbraccia, Paolo; Novelli, Giuseppe; Turnpenny, Peter D.; McCann, Emma; Goh, Kim Jee; Wang, Yukai; Fulford, Jonathan; McCulloch, Laura; Savage, David B.; O’Rahilly, Stephen; Kos, Katarina; Loeb, Lawrence A.; Semple, Robert K.; Hattersley, Andrew T.

doi:10.1038/ng.2670

Cited by 153 publications

(167 citation statements)

References 30 publications

Supporting

Mentioning

164

Contrasting

Order By: Relevance

“…Each of these genes plays some role in permitting dividing cells to tolerate DNA damage and in the maintenance of telomeres. Another recently described syndrome featuring loss of s.c. fat as well as severe IR is caused by heterozygous loss-of-function mutations in POLD1, encoding DNA polymerase delta, the dominant lagging strand DNA synthase in human cells (51). This adds to the impression that some aspects of DNA damage repair or replication are critical to metabolic homeostasis.…”

Section: Complex Monogenic Disorders Featuring Severe Irmentioning

confidence: 99%

EJE PRIZE 2015: How does insulin resistance arise, and how does it cause disease? Human genetic lessons

Semple¹

2016

European Journal of Endocrinology

View full text Add to dashboard Cite

Insulin orchestrates physiological responses to ingested nutrients; however, although it elicits widely ramifying metabolic and trophic responses from diverse tissues, 'insulin resistance (IR)', a pandemic metabolic derangement commonly associated with obesity, is usually defined solely by blunting of insulin's hypoglycaemic effect. Recent study of monogenic forms of IR has established that biochemical subphenotypes of IR exist, clustering into those caused by primary disorders of adipose tissue and those caused by primary defects in proximal insulin signalling. IR is often first recognised by virtue of its associated disorders including type 2 diabetes, dyslipidaemia (DL), fatty liver and polycystic ovary syndrome (PCOS). Although these clinically observed associations are confirmed by cross-sectional and longitudinal population-based studies, causal relationships among these phenomena have been more difficult to establish. Single gene IR is important to recognise in order to optimise clinical management and also permits testing of causal relationships among components of the IR syndrome using the principle of Mendelian randomisation. Thus, where a precisely defined genetic defect is identified that directly produces one component of the syndrome, then phenomena that are causally linked to that component should be seen. Where this is not the case, then a simple causal link is refuted. This article summarises known forms of monogenic severe IR and considers the lessons to be learned about the pathogenic mechanisms both upstream from common IR and those downstream linking it to disorders such as DL, fatty liver, PCOS and cancer.

show abstract

Section: Complex Monogenic Disorders Featuring Severe Irmentioning

confidence: 99%

EJE PRIZE 2015: How does insulin resistance arise, and how does it cause disease? Human genetic lessons

Semple¹

2016

European Journal of Endocrinology

View full text Add to dashboard Cite

show abstract

“…39 Individuals with rare genetic diseases that accelerate aging, such as Werner or MDP (Mandibular hypoplasia, Deafness and Progeroid features) syndromes are also known to develop tissue degeneration that affects many organs including the pancreatic gland. Intriguingly, these two syndromes are the result of mutations in genes involved in DNA replication, WRN helicase and DNA polymerase δ catalytic subunit encoding gene POLD1, respectively, 40,41 suggesting that DNA replication stress, such as that exhibited by E2F1/2-deficient cells, may drive tissue involution and aging in some pathological conditions. E2F1 and E2F2 represent controversial players in cell-cycle control, exhibiting dual behavior as tumor suppressors or as oncogenes.…”

Section: E2f-p53 Regulatory Axis In Tissue Homeostasismentioning

confidence: 99%

E2F1 and E2F2 prevent replicative stress and subsequent p53-dependent organ involution

et al. 2015

View full text Add to dashboard Cite

Tissue homeostasis requires tight regulation of cellular proliferation, differentiation and apoptosis. E2F1 and E2F2 transcription factors share a critical role in tissue homeostasis, since their combined inactivation results in overall organ involution, specially affecting the pancreatic gland, which subsequently triggers diabetes. We have examined the mechanism by which these E2Fs regulate tissue homeostasis. We show that pancreas atrophy in E2F1/E2F2 double-knockout (DKO) mice is associated with mitochondrial apoptosis and activation of the p53 pathway in young animals, before the development of diabetes. A deregulated expression of E2F target genes was detected in pancreatic cells of young DKO animals, along with unscheduled DNA replication and activation of a DNA damage response. Importantly, suppression of DNA replication in vivo with aphidicolin led to a significant inhibition of the p53 pathway in DKO pancreas, implying a causal link between DNA replication stress and p53 activation in this model. We further show that activation of the p53 pathway has a key role in the aberrant phenotype of DKO mice, since targeted inactivation of p53 gene abrogated cellular apoptosis and prevented organ involution and insulin-dependent diabetes in mice lacking E2F1/E2F2. Unexpectedly, p53 inactivation unmasked oncogenic features of E2F1/E2F2-depleted cells, as evidenced by an accelerated tumor development in triple-knockout mice compared with p53 − / − mice. Collectively, our data reveal a role for E2F1 and E2F2 as suppressors of replicative stress in differentiating cells, and uncover the existence of a robust E2F-p53 regulatory axis to enable tissue homeostasis and prevent tumorigenesis. These findings have implications in the design of approaches targeting E2F for cancer therapy.

show abstract

“…One aspect of the association between PCOS and SSIR is that, in the last two decades, it has become increasingly clear that the responsible genetic factors of PCOS linked to SSIR are quite specific, and completely different with respect to the susceptible genes of the common PCOS, as proposed by recent genome-wide association and linkage studies (22,23). In fact, a combination of linkage analysis and candidate gene screening has led to the identification of a list of genes associated with congenital lipodystrophy, either generalized or partial, that encodes protein essential for normal fat tissue development and/or function in Recently, two new inherited forms of lipodystrophies due to mutation in polymerase delta 1 (POLD1) or hormonesensitive lipase (LIPE) gene have been described (70,71). The expanding genetic background responsible for the development of the different lipodystrophy phenotypes indirectly supports the primary role of exaggerated circulating insulin in the development of the forms of secondary PCOS in these patients.…”

Section: Severe Insulin-resistant Syndrome and Pcosmentioning

confidence: 99%

MANAGEMENT OF ENDOCRINE DISEASE: Secondary polycystic ovary syndrome: theoretical and practical aspects

Pasquali

Diamanti-Kandarakis

Gambineri

2016

European Journal of Endocrinology

View full text Add to dashboard Cite

PCOS is a clinical heterogeneous entity of female androgen excess diagnosed by exclusion of other disorders responsible for androgen excess. The concept of secondary PCOS implies that there is a primary well-defined cause leading to the PCOS phenotype with underlying androgen overproduction, regardless of the origin. In these cases, we presume the term of 'secondary PCOS' could be used. In all these conditions, the potential complete recovery of the hyperandrogenemic state as well as the remission of the PCOS phenotype should follow the removal of the cause. If accepted, these concepts could help clinicians to perform in-depth investigations of the potential factors or disorders responsible for the development of these specific forms of secondary PCOS. Additionally, this could contribute to develop further research on factors and mechanisms involved in the development of the classic and the nonclassic PCOS phenotypes. Invited author's profileRenato Pasquali is full professor of Endocrinology & Metabolism and Director of the division of Endocrinology of the S.Orsola-Malpighi Hospital, Bologna, Italy. He also heads the School of Specialization in Endocrinology and Metabolism, University Alma Mater Studiorum of Bologna, Italy. He is a member of numerous national and international scientific societies and serves on the editorial boards of international journals. His scientific interests relate to (i) the pathophysiology and treatment of the polycystic ovary syndrome; (ii) the endocrinology of obesity (sex hormones, the hypothalamic-pituitary-adrenal axis, and the endocannabinoid system).

show abstract

An in-frame deletion at the polymerase active site of POLD1 causes a multisystem disorder with lipodystrophy

Cited by 153 publications

References 30 publications

EJE PRIZE 2015: How does insulin resistance arise, and how does it cause disease? Human genetic lessons

EJE PRIZE 2015: How does insulin resistance arise, and how does it cause disease? Human genetic lessons

E2F1 and E2F2 prevent replicative stress and subsequent p53-dependent organ involution

MANAGEMENT OF ENDOCRINE DISEASE: Secondary polycystic ovary syndrome: theoretical and practical aspects

Contact Info

Product

Resources

About