The Role of Epigenetics in Type 1 Diabetes Jerram, Samuel T.; Dang, Mary N.; Leslie, R. David
Current diabetes reports,
10/2017, Letnik:
17, Številka:
10
Journal Article
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Purpose of Review
Epigenetics is defined as mitotically heritable changes in gene expression that do not directly alter the DNA sequence. By implication, such epigenetic changes are non-genetically ...determined, although they can be affected by inherited genetic variation. Extensive evidence indicates that autoimmune diseases including type 1 diabetes are determined by the interaction of genetic and non-genetic factors. Much is known of the genetic causes of these diseases, but the non-genetic effects are less clear-cut. Further, it remains unclear how they interact to cause the destructive autoimmune process. This review identifies the key issues in the genetic/non-genetic interaction, examining the most recent evidence of the role of non-genetic effects in the disease process, including the impact of epigenetic effects on key pathways.
Recent Findings
Recent research indicates that these pathways likely involve immune effector cells both of the innate and adaptive immune response. Specifically, there is evidence of cell type-specific enrichment in altered DNA methylation, changes which were temporally stable and enriched at gene regulatory elements.
Summary
Epigenomics remains in its infancy, and we anticipate further studies will define how the interaction of genetic and non-genetic effects induces tissue-specific destruction and enhances our ability to predict, and possibly even modify that process.
The β-cell–enriched MAFA transcription factor plays a central role in regulating glucose-stimulated insulin secretion while also demonstrating oncogenic transformation potential in vitro. No ...disease-causing MAFA variants have been previously described. We investigated a large pedigree with autosomal dominant inheritance of diabetes mellitus or insulinomatosis, an adult-onset condition of recurrent hyperinsulinemic hypoglycemia caused by multiple insulin-secreting neuroendocrine tumors of the pancreas. Using exome sequencing, we identified a missense MAFA mutation (p.Ser64Phe, c.191C>T) segregating with both phenotypes of insulinomatosis and diabetes. This mutation was also found in a second unrelated family with the same clinical phenotype, while no germline or somatic MAFA mutations were identified in nine patients with sporadic insulinomatosis. In the two families, insulinomatosis presented more frequently in females (eight females/two males) and diabetes more often in males (12 males/four females). Four patients from the index family, including two homozygotes, had a history of congenital cataract and/or glaucoma. The p.Ser64Phe mutation was found to impair phosphorylation within the transactivation domain of MAFA and profoundly increased MAFA protein stability under both high and low glucose concentrations in β-cell lines. In addition, the transactivation potential of p.Ser64Phe MAFA in β-cell lines was enhanced compared with wild-type MAFA. In summary, the p.Ser64Phe missense MAFA mutation leads to familial insulinomatosis or diabetes by impacting MAFA protein stability and transactivation ability. The human phenotypes associated with the p.Ser64Phe MAFA missense mutation reflect both the oncogenic capacity of MAFA and its key role in islet β-cell activity.
Predictive tools to identify patients at risk for gene mutations related to pituitary adenomas are very helpful in clinical practice. We therefore aimed to develop and validate a reliable risk ...category system for aryl hydrocarbon receptor-interacting protein (
) mutations in patients with pituitary adenomas.
An international cohort of 2227 subjects were consecutively recruited between 2007 and 2016, including patients with pituitary adenomas (familial and sporadic) and their relatives. All probands (n=1429) were screened for
mutations, and those diagnosed with a pituitary adenoma prospectively, as part of their clinical screening (n=24), were excluded from the analysis. Univariate analysis was performed comparing patients with and without
mutations. Based on a multivariate logistic regression model, six potential factors were identified for the development of a risk category system, classifying the individual risk into low-risk, moderate-risk and high-risk categories. An internal cross-validation test was used to validate the system.
1405 patients had a pituitary tumour, of which 43% had a positive family history, 55.5% had somatotrophinomas and 81.5% presented with macroadenoma. Overall, 134 patients had an
mutation (9.5%). We identified four independent predictors for the presence of an
mutation: age of onset providing an odds ratio (OR) of 14.34 for age 0-18 years, family history (OR 10.85), growth hormone excess (OR 9.74) and large tumour size (OR 4.49). In our cohort, 71% of patients were identified as low risk (<5% risk of
mutation), 9.2% as moderate risk and 20% as high risk (≥20% risk). Excellent discrimination (c-statistic=0.87) and internal validation were achieved.
We propose a user-friendly risk categorisation system that can reliably group patients into high-risk, moderate-risk and low-risk groups for the presence of
mutations, thus providing guidance in identifying patients at high risk of carrying an
mutation. This risk score is based on a cohort with high prevalence of
mutations and should be applied cautiously in other populations.
Non-syndromic pituitary gigantism can result from AIP mutations or the recently identified Xq26.3 microduplication causing X-linked acrogigantism (XLAG). Within Xq26.3, GPR101 is believed to be the ...causative gene, and the c.924G > C (p.E308D) variant in this orphan G protein-coupled receptor has been suggested to play a role in the pathogenesis of acromegaly.We studied 153 patients (58 females and 95 males) with pituitary gigantism. AIP mutation-negative cases were screened for GPR101 duplication through copy number variation droplet digital PCR and high-density aCGH. The genetic, clinical and histopathological features of XLAG patients were studied in detail. 395 peripheral blood and 193 pituitary tumor DNA samples from acromegaly patients were tested for GPR101 variants.We identified 12 patients (10 females and 2 males; 7.8 %) with XLAG. In one subject, the duplicated region only contained GPR101, but not the other three genes in found to be duplicated in the previously reported patients, defining a new smallest region of overlap of duplications. While females presented with germline mutations, the two male patients harbored the mutation in a mosaic state. Nine patients had pituitary adenomas, while three had hyperplasia. The comparison of the features of XLAG, AIP-positive and GPR101&AIP-negative patients revealed significant differences in sex distribution, age at onset, height, prolactin co-secretion and histological features. The pathological features of XLAG-related adenomas were remarkably similar. These tumors had a sinusoidal and lobular architecture. Sparsely and densely granulated somatotrophs were admixed with lactotrophs; follicle-like structures and calcifications were commonly observed. Patients with sporadic of familial acromegaly did not have an increased prevalence of the c.924G > C (p.E308D) GPR101 variant compared to public databases.In conclusion, XLAG can result from germline or somatic duplication of GPR101. Duplication of GPR101 alone is sufficient for the development of XLAG, implicating it as the causative gene within the Xq26.3 region. The pathological features of XLAG-associated pituitary adenomas are typical and, together with the clinical phenotype, should prompt genetic testing.
We present the first case of pituitary carcinoma occurring in a patient with a succinate dehydrogenase subunit B
(SDHB)
mutation and history of paraganglioma. She was initially treated for a glomus ...tumour with external beam radiotherapy. Twenty-five years later, she was diagnosed with a non-functioning pituitary adenoma, having developed bitemporal hemianopia. Recurrence of the pituitary lesion (Ki-67 10% and p53 overexpressed) occurred 5 years after her transsphenoidal surgery, for which she underwent two further operations followed by radiotherapy. Histology showed large cells with vacuolated clear cytoplasm with positive immunostaining for steroidogenic factor 1 (SF1) and negative staining for pituitary hormones. Four years after the pituitary radiotherapy, two metastatic deposits were identified: a foramen magnum lesion and an intradural extra-medullary cervical lesion at the level of C3/C4. There was also significant growth of the primary pituitary lesion with associated visual deterioration. A biopsy of the foramen magnum lesion, demonstrating cells with vacuolated, clear cytoplasm and positive SF1 staining confirmed a pituitary carcinoma, for which she was commenced on temozolomide chemotherapy. There was dramatic clinical improvement after three cycles and reduction in the size of the lesions was observed following six cycles of temozolomide, and further shrinkage after 10 cycles. The plan is for a total of 12 cycles of temozolomide chemotherapy.
SDH
mutation-related pituitary tumours have an aggressive phenotype which, in this case, led to metastatic disease. SF1 immunostaining was helpful to identify the tissue origin of the metastatic deposit and to confirm the pituitary carcinoma.
Type 4 phosphodiesterases (PDE4s) of the large PDE enzyme superfamily have unique specificity for cAMP and may, therefore, be relevant for somatotroph tumorigenesis. Somatotroph adenomas typically ...overexpress PDEs probably as part of a compensatory mechanism to reduce cAMP levels. The rat PDE4A5 isoform (human homolog PDE4A4) interacts with the AIP protein, coded by a tumour suppressor gene mutated in a subgroup of familial isolated pituitary adenomas (FIPAs). PDE4A8 is the closest related isoform of PDE4A4. We aimed to evaluate the expression of both PDE4A4 and PDE4A8 in GH cells of AIP-mutated adenomas and compare their expression with that in GH cells from sporadic AIP-mutation negative GH-secreting adenomas, where we had shown previously that both PDE4A4 and PDE4A8 isoforms had been over-expressed. Confocal immunofluorescence analysis showed that both PDE4A8 and PDE4A4 had lower expression in AIP-mutated somatotropinoma samples compared to sporadic GH-secreting tumours (P < 0.0001 for both). Based on the association of low PDE4A4 and PDE4A8 expression with germline AIP-mutations positive samples we suggest that lack of AIP hinders the upregulation of PDE4A8 and PDE4A4 protein seen in sporadic somatotrophinomas. These data point to a unique disturbance of the cAMP-PDE pathway in AIP-mutation positive adenomas, which may help to explain their well-described poor response to somatostatin analogues.
•Somatotroph adenomas overexpress PDE4A4 and PDE4A8, probably as compensatory mechanism to reduce cAMP levels.•PDE4A5 interacts with AIP while PDE4A8 is its closest related isoform.•The lack of AIP in AIP-mutation positive samples hinders the upregulation of both PDE4A4 and PDE4A8.•Disturbance of the cAMP-PDE pathway in AIP-positive adenomas may contribute to the poor response to somatostatin analogues.
Abstract
Pituitary adenomas are usually benign tumours arising from the hormone-secreting cells of the anterior pituitary gland, resulting in excess hormone secretion and the development of ...characteristic syndromes, such as Cushing’s disease, acromegaly and hyperprolactinaemia, and/or mass effects on surrounding vital structures causing for example visual disturbances and pituitary hormone deficiencies. In children and young people under 19 years (CYP), the management of pituitary adenomas is particularly challenging given their extreme rarity, more aggressive phenotype and likely genetic predisposition, as well as the lack of age- and pituitary-specific multidisciplinary teams in current decision-making and service provision. Hence, the UK sought to create national, high-quality, multi-professional guidance using AGREE II methodology under the auspices of the UK paediatric endocrine (BSPED), paediatric oncology (CCLG) and paediatric (RCPCH) societies. Twenty geographically diverse experts in adult and paediatric endocrinology, neuroradiology, clinical oncology, neurosurgery, paediatric neuropathology, and neuro-ophthalmology constituted the guideline development group and formulated 155 clinical questions. Following a systematic literature review of 409 identified papers dating from 1990 to 2016, the group made 56 evidence-based recommendations for biochemical, radiological, cytological, genetic, and ophthalmic assessment of suspected pituitary adenomas as well as surgical and oncological treatment, and follow-up. A further 55 recommendations were made based on group expert opinion and were reviewed by two rounds of an international Delphi expert consensus process. This guideline should facilitate improved clinical care and outcomes in CYP with pituitary adenomas.
Context
Pseudoacromegaly describes conditions with an acromegaly related physical appearance without abnormalities in the growth hormone (GH) axis. Acromegaloid facies, together with hypertrichosis, ...are typical manifestations of Cantú syndrome.
Case description
We present a three-generation family with 5 affected members, with marked acromegaloid facies and prominent hypertrichosis, due to a novel missense variant in the
ABCC9
gene. The proband, a 2-year-old girl, was referred due to marked hypertrichosis, noticed soon after birth, associated with coarsening of her facial appearance. Her endocrine assessment, including of the GH axis, was normal. The proband's father, paternal aunt, and half-sibling were referred to the Endocrine department for exclusion of acromegaly. Although the GH axis was normal in all, two subjects had clinically non-functioning pituitary macroadenomas, a feature which has not previously been associated with Cantú syndrome.
Conclusions
Activating mutations in the
ABCC9
and, less commonly,
KCNJ8
genes—representing the two subunits of the ATP-sensitive potassium channel—have been linked with Cantú syndrome. Interestingly, minoxidil, a well-known ATP-sensitive potassium channel agonist, can cause a similar phenotype. There is no clear explanation why activating this channel would lead to acromegaloid features or hypertrichosis. This report raises awareness for this complex condition, especially for adult or pediatric endocrinologists who might see these patients referred for evaluation of acromegaloid features or hirsutism. The link between Cantú syndrome and pituitary adenomas is currently unclear.
Epigenetics provides a mechanism in which the environment can interact with the genotype to produce a variety of phenotypes. These epigenetic modifications have been associated with altered gene ...expression and silencing of repetitive elements, and these modifications can be inherited mitotically. DNA methylation is the best characterized epigenetic mark and earlier studies have examined DNA methylation profiles in peripheral blood mononuclear cells in disease. However, any disease-related signatures identified would just display differences in the relative abundance of individual cell types as each cell subset generates a unique methylation profile. Therefore is it important to identify cell- or tissue-specific changes in DNA methylation, particularly in autoimmune diseases such as type 1 diabetes.
The incidence of type 1 diabetes (T1D) has substantially increased over the past decade, suggesting a role for non-genetic factors such as epigenetic mechanisms in disease development. Here we ...present an epigenome-wide association study across 406,365 CpGs in 52 monozygotic twin pairs discordant for T1D in three immune effector cell types. We observe a substantial enrichment of differentially variable CpG positions (DVPs) in T1D twins when compared with their healthy co-twins and when compared with healthy, unrelated individuals. These T1D-associated DVPs are found to be temporally stable and enriched at gene regulatory elements. Integration with cell type-specific gene regulatory circuits highlight pathways involved in immune cell metabolism and the cell cycle, including mTOR signalling. Evidence from cord blood of newborns who progress to overt T1D suggests that the DVPs likely emerge after birth. Our findings, based on 772 methylomes, implicate epigenetic changes that could contribute to disease pathogenesis in T1D.
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