First phase insulin release and glucose tolerance in children with Fanconi anemia after hematopoietic cell transplantation

Polgreen, Lynda E.; Thomas, William; MacMillan, Margaret L.; Wagner, John E.; Moran, Antoinette; Petryk, Anna

doi:10.1002/pbc.22043

Cited by 11 publications

(7 citation statements)

References 19 publications

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“…This is in line with our present findings that DUT knockdown triggers apoptosis of human and rat b-cells, with the altered pancreatic islet histology of patient 2 and the very low insulin secretion in patient 1. Glucose metabolism and insulin secretion are frequently impaired in diseases associated with DNA repair defects, including FA (34,35) and Bloom syndrome (36). DNA damage and genomic instability have been shown to alter b-cell replication through cell-cycle inhibition, leading to impaired glucose metabolism and diabetes (36,37).…”

Section: Discussionmentioning

confidence: 99%

dUTPase (DUT) Is Mutated in a Novel Monogenic Syndrome With Diabetes and Bone Marrow Failure

et al. 2017

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We describe a new syndrome characterized by early-onset diabetes associated with bone marrow failure, affecting mostly the erythrocytic lineage. Using whole-exome sequencing in a remotely consanguineous patient from a family with two affected siblings, we identified a single homozygous missense mutation (chr15.hg19:g.48,626,619A>G) located in the dUTPase () gene (National Center for Biotechnology Information Gene ID 1854), affecting both the mitochondrial (DUT-M p.Y142C) and the nuclear (DUT-N p.Y54C) isoforms. We found the same homozygous mutation in an unrelated consanguineous patient with diabetes and bone marrow aplasia from a family with two affected siblings, whereas none of the >60,000 subjects from the Exome Aggregation Consortium (ExAC) was homozygous for this mutation. This replicated observation probability was highly significant, thus confirming the role of this mutation in this syndrome. DUT is a key enzyme for maintaining DNA integrity by preventing misincorporation of uracil into DNA, which results in DNA toxicity and cell death. We showed that DUT silencing in human and rat pancreatic β-cells results in apoptosis via the intrinsic cell death pathway. Our findings support the importance of tight control of DNA metabolism for β-cell integrity and warrant close metabolic monitoring of patients treated by drugs affecting dUTP balance.

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Section: Discussionmentioning

confidence: 99%

dUTPase (DUT) Is Mutated in a Novel Monogenic Syndrome With Diabetes and Bone Marrow Failure

et al. 2017

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“…Giri et al [23] evaluated 45 patients with FA, 9 of whom underwent HCT: 37% had hypothyroidism, 50% of males had hypogonadism and 69% females had premature ovarian failure. Other observed endocrinopathies after HCT include lower BMD [33] and insulin resistance [34] but data in patients with FA after HCT remain limited.…”

Section: Discussionmentioning

confidence: 99%

Endocrinopathies, Bone Health, and Insulin Resistance in Patients with Fanconi Anemia after Hematopoietic Cell Transplantation

Barnum

Petryk

Zhang

et al. 2016

Biology of Blood and Marrow Transplantation

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A number of endocrinopathies have been described after hematopoietic cell transplantation (HCT), but data are limited in patients with Fanconi anemia (FA). We report several endocrine-based disorders in a cohort of 44 patients with FA after HCT compared with both 74 patients who received HCT for hematologic malignancies and with 275 healthy controls. Endocrinopathies assessed included hypothyroidism, hypogonadism, short stature, dyslipidemia, insulin resistance, abnormalities in body composition, and bone health. Most (86%) patients with FA had at least 1 endocrinopathy, with 11% having 3 or more. Hypothyroidism was seen in 57%, hypogonadism in 27%, short stature in 50%, and reduced total body and lumbar spine bone mineral density (BMD) (height adjusted Z-score < −1) in 57% and 21%, respectively. Vitamin D deficiency was seen in 71%. Short stature was associated with younger age at HCT and gonadal failure was associated with older age at HCT. Insulin resistance was associated with increased percent fat mass and increased android/gynoid ratio by dual energy X-ray absorptiometry. Hypothyroidism, short stature, and reduced total body BMD were more prevalent in patients with FA compared with patients with hematologic malignancies. We recommend an assessment before transplantation and close follow-up afterwards to ensure proper clinical management. Future studies should continue to explore the impact of HCT on endocrinopathies in FA patients.

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“…Certain endocrinopathies have been found to be common in FA. These include mild primary hypothyroidism, central hypothyroidism, growth hormone secretory dysfunction, and beta cell dysfunction with deficient insulin release leading to glucose intolerance and/or diabetes mellitus 2–5, 7, 12. In addition, puberty may be delayed, males may have small gonads and infertility, and females may experience early menopause.…”

Section: Introductionmentioning

confidence: 99%

Bone mineral density is normal in children with Fanconi anemia

Rose

Rutter

Mueller

et al. 2011

Pediatric Blood & Cancer

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First phase insulin release and glucose tolerance in children with Fanconi anemia after hematopoietic cell transplantation

Abstract: Background-Fanconi anemia (FA) is an autosomal and X-linked recessive disease of chromosomal instability which results in bone marrow failure. Children with FA have been shown to have an increased risk of diabetes mellitus (DM).

Cited by 11 publications

References 19 publications

dUTPase (DUT) Is Mutated in a Novel Monogenic Syndrome With Diabetes and Bone Marrow Failure

dUTPase (DUT) Is Mutated in a Novel Monogenic Syndrome With Diabetes and Bone Marrow Failure

Endocrinopathies, Bone Health, and Insulin Resistance in Patients with Fanconi Anemia after Hematopoietic Cell Transplantation

Bone mineral density is normal in children with Fanconi anemia

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