Phenotype variability and neonatal diabetes in a large family with heterozygous mutation of the glucokinase gene

Monogenic diabetes caused by mutations in the glucokinase gene (GCK-MODY) is usually characterized by a mild clinical phenotype. The clinical course of diabetes may be, however, highly variable. The authors present a child with diabetes manifesting with ketoacidosis during the neonatal period, born in a large family with ten members bearing a heterozygous p.Gly223Ser mutation in GCK. DNA sequencing and multiplex ligation-dependent probe amplification were used to confirm GCK mutation and exclude other de novo mutations in other known genes associated with monogenic diabetes. Continuous glucose monitoring (CGM) was used to assess daily glycemic profiles. At the onset of diabetes the child had hyperglycemia 765 mg/dl with pH 7.09. Her glycated hemoglobin level was 8.6% (70.5 mmol/mol). The C-peptide level was below normal range (<0.5 pmol/ml) at onset, and the three- and 6-month follow-up examinations. Current evaluation at age 3 still showed unsatisfactory metabolic control with HbA1c level equal to 8.1% (65.0 mmol/mol). CGM data showed glucose concentrations profile similar to poorly controlled type 1 diabetes. The patient was confirmed to be heterozygous for the p.Gly223Ser mutation and did not show any point mutations or deletions within other monogenic diabetes genes. Other family members with p.Gly223Ser mutation had retained C-peptide levels and mild diabetes manageable with diet (five individuals), oral hypoglycemizing agents (five patients), or insulin (one patient). This mutation was absent within all healthy family members. Heterozygous mutations of the GCK gene may result in neonatal diabetes similar to type 1 diabetes, the cause of such phenotype variety is still unknown. The possibility of other additional, unknown mutations seems to be the most likely explanation for the unusual presentation of GCK-MODY

The role of histone protein modifications and mutations in histone modifiers in pediatric b-cell progenitor acute lymphoblastic leukemia

While cancer has been long recognized as a disease of the genome, the importance of epigenetic mechanisms in neoplasia was acknowledged more recently. The most active epigenetic marks are DNA methylation and histone protein modifications and they are involved in basic biological phenomena in every cell. Their role in tumorigenesis is stressed by recent unbiased large-scale studies providing evidence that several epigenetic modifiers are recurrently mutated or frequently dysregulated in multiple cancers. The interest in epigenetic marks is especially due to the fact that they are potentially reversible and thus druggable. In B-cell progenitor acute lymphoblastic leukemia (BCP-ALL) there is a relative paucity of reports on the role of histone protein modifications (acetylation, methylation, phosphorylation) as compared to acute myeloid leukemia, T-cell ALL, or other hematologic cancers, and in this setting chromatin modifications are relatively less well studied and reviewed than DNA methylation. In this paper, we discuss the biomarker associations and evidence for a driver role of dysregulated global and loci-specific histone marks, as well as mutations in epigenetic modifiers in BCP-ALL. Examples of chromatin modifiers recurrently mutated/disrupted in BCP-ALL and associated with disease outcomes include MLL1, CREBBP, NSD2, and SETD2. Altered histone marks and histone modifiers and readers may play a particular role in disease chemoresistance and relapse. We also suggest that epigenetic regulation of B-cell differentiation may have parallel roles in leukemogenesis

Severe hypertriglyceridemia in the course of ketoacidosis in a patient with newly diagnosed type 1 diabetes mellitus

BACKGROUND: One of the most serious complications in delayed diagnosis of DKA is hypertriglyceridemia (HTG), Prevalence of mild hypertriglyceridemia is found in about 50% of patients with diabetic ketoacidosis (DKA). Prevalence of severe hypertriglyceridemia [TG &gt; 22.4 mmol/L (&gt; 1959 mg/dL)] was found in about 1–8% of adults with DKA, but few data have been reported in children with severity ranging from asymptomatic to severe acute pancreatitis.CASE PRESENTATION: A 2-year-old-girl with a 2 weeks history of generalized weakness, polydipsia, polyuria, and vulvar candidiasis was admitted to the Intensive Care Unit with clinical signs of DKA. Our patient was met the diagnostic criteria for DKA (pH 7.1, HCO3- 8.8 mmol/L, BE -21.1 mmol/L), glucose level of &gt; 22 mmol/L (556 mg/dl). Initial biochemical analysis showed hyperlipidemia [TG 11470 mg/dL (131.1 mmol/L)], amylase 28 U/L. Her blood demonstrated a grossly lipemic appearance and her lipemic condition disturbed the results of other biochemical blood investigations. The objective of this case report is to present and describe the clinical features, laboratory investigations, case management, and natural course of hypertriglyceridemia in a 2-year-old girl with DKA.CONCLUSIONS: Lipemia secondary to severe HTG may exist in new-onset T1DM with DKA. Diabetic lipemia can be caused not only by profound insulin deficiency. An additional factor which should be taken into consideration in very young children is breastfeeding, which is associated with increased mean total cholesterol (TC) and LDL levels. Moreover, severe hypertriglyceridemia may result in mutations of genes encoding lipoprotein lipase (LPL)

Genetic polymorphisms in DNA base excision repair gene XRCC1 and the risk of squamous cell carcinoma of the head and neck

<p>Abstract</p> <p>Background</p> <p>The genes of base excision repair (BER) pathway have been extensively studied in the association with various human cancers. We performed a case-control study to test the association between two common single nucleotide polymorphisms (SNPs) of <it>XRCC1 </it>gene with human head and neck squamous cell carcinoma (HNSCC).</p> <p>Methods</p> <p>The genotype analysis of Arg194Trp and Arg399Gln gene polymorphisms for 92 HNSCC patients and 124 controls of cancer free subjects, in Polish population were performed using the PCR-based restriction fragment length polymorphism (PCR-RFLP) with endonuclease <it>Msp</it>I.</p> <p>Results</p> <p>No altered risk has been found individually for these SNPs, however haplotypes analysis showed high association with head and neck cancer. The highest frequency, according to wild-type of Arg194Arg and Arg399Arg genotypes, was identified for Arg194Trp-Arg399Arg haplotype (OR, 2.96; 95% CI, 1.01–8.80).</p> <p>Conclusion</p> <p>Finally, we identified the combined Arg194Trp-Arg399Arg genotype of base excision repair gene <it>XRCC1 </it>that was associated with HNSCC and may have an impact on identification of a high-risk cancer population.</p

Influence of genomic variation in FTO at 16q12.2, MC4R at 18q22 and NRXN3 at 14q31 genes on breast cancer risk

Breast cancer is a major cause of cancer-related deaths in women. It is known that obesity is one of the risk factors of breast cancer. The subject of our interest was genes: FTO, MC4R and NRXN3–associated with obesity. In this study we have analyzed frequencies of genomic variants in FTO, MC4R and NRXN3 in the group of 134 breast cancer patients. We genotyped two polymorphic sites located in FTO gene (rs993909 and rs9930506), one polymorphic site of MC4R gene (rs17782313) and one polymorphic site of NRXN3 gene (rs10146997). Our hypothesis was that above mentioned SNPs could participate in carcinogenesis. Our research has showed that only rs10146997 was significantly (P = 0.0445) associated with higher risk of breast cancer development (OR = 0.66 (95% CI 0.44–0.99)). Moreover, G allele carriers in rs10146997 of the NRXN3 gene were the youngest patients at onset of breast cancer. On the basis of our research we suggest that further functional may elucidate the role of genomic variation in breast cancer development

MLL-rearranged B lymphoblastic leukemias selectively express the immunoregulatory carbohydrate-binding protein galectin-1

Leukemias with 11q23 translocations involving the Mixed Lineage Leukemia (MLL) gene exhibit unique clinical and biological features and have a poor prognosis. In a screen for molecular markers of MLL rearrangement, we identified the specific overexpression of an immunomodulatory lectin Galectin-1 (Gal1) in MLL-rearranged B lymphoblastic leukemias (B-ALL) compared to other MLL-germline ALLs. To assess the diagnostic utility of Gal1 expression in identifying MLL-rearranged B-ALLs, we performed Gal1 immunostaining on a large series of primary ALLs with known MLL status. All 11 MLL-rearranged B-ALLs had abundant Gal1 expression; in marked contrast, only 1 of 42 germline-MLL B-ALLs expressed Gal1. In addition, Gal1 was readily detected in diagnostic samples of MLL-rearranged B-ALLs by intracellular flow cytometry. Since deregulated gene expression in MLL-rearranged leukemias may be related to the altered histone methyltransferase activity of MLL fusion protein complex, we analyzed histone H3 lysine 79 (H3K79) dimethylation in the Gal1 promoter region using chromatin immunoprecipitation. Gal1 promoter H3K79diMe was ≈ 5 fold higher in a MLL-rearranged B-ALL cell line than in a B-ALL line without the MLL translocation. Furthermore, the Gal1 promoter H3K79 was significantly hypermethylated in primary MLL-rearranged B-ALLs compared to MLL-germline B-ALLs and normal pre-B cells, implicating this epigenetic modification as a mechanism for Gal1 overexpression in MLL B-ALL.Fil: Juszczynski, Przemyslaw. Dana Farber Cancer Institute; Estados UnidosFil: Rodig, Scott J.. Brigham & Women; Estados UnidosFil: Ouyang, Jing. Dana Farber Cancer Institute; Estados UnidosFil: O´Donnell, Evan. Dana Farber Cancer Institute; Estados UnidosFil: Takeyama, Kunihiko. Dana Farber Cancer Institute; Estados UnidosFil: Mlynarski, Wojciech. Dana Farber Cancer Institute; Estados UnidosFil: Mycko, Katarzyna. Dana Farber Cancer Institute; Estados UnidosFil: Szczepanski, Tomasz. Dana Farber Cancer Institute; Estados UnidosFil: Gaworczyk, Anna. Medical University of Lodz; PoloniaFil: Krivtsov, Andrei. Medical University of Lodz; PoloniaFil: Faber, Joerg. Medical University of Silesia; PoloniaFil: Sinha, Amit U.. Medical University of Lublin; PoloniaFil: Rabinovich, Gabriel Adrian. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina; ArgentinaFil: Armstrong, Scott A.. Children; Estados UnidosFil: Kutok, Jeffery. Children; Estados UnidosFil: Shipp, Margaret A.. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina; Argentin

Differential regulation of serum microRNA expression by HNF1β and HNF1α transcription factors.

We aimed to identify microRNAs (miRNAs) under transcriptional control of the HNF1β transcription factor, and investigate whether its effect manifests in serum.This article is freely available via Open Access. Click on the 'Additional Link' above to access the full-text via the publisher's site.Published (Open Access

Validation of the United Kingdom copy-number alteration classifier in 3239 children with B-cell precursor ALL

Genetic abnormalities provide vital diagnostic and prognostic information in pediatric acute lymphoblastic leukemia (ALL) and are increasingly used to assign patients to risk groups. We recently proposed a novel classifier based on the copy-number alteration (CNA) profile of the 8 most commonly deleted genes in B-cell precursor ALL. This classifier defined 3 CNA subgroups in consecutive UK trials and was able to discriminate patients with intermediate-risk cytogenetics. In this study, we sought to validate the United Kingdom ALL (UKALL)-CNA classifier and reevaluate the interaction with cytogenetic risk groups using individual patient data from 3239 cases collected from 12 groups within the International BFM Study Group. The classifier was validated and defined 3 risk groups with distinct event-free survival (EFS) rates: good (88%), intermediate (76%), and poor (68%) (P < .001). There was no evidence of heterogeneity, even within trials that used minimal residual disease to guide therapy. By integrating CNA and cytogenetic data, we replicated our original key observation that patients with intermediate-risk cytogenetics can be stratified into 2 prognostic subgroups. Group A had an EFS rate of 86% (similar to patients with good-risk cytogenetics), while group B patients had a significantly inferior rate (73%, P < .001). Finally, we revised the overall genetic classification by defining 4 risk groups with distinct EFS rates: very good (91%), good (81%), intermediate (73%), and poor (54%), P < .001. In conclusion, the UKALL-CNA classifier is a robust prognostic tool that can be deployed in different trial settings and used to refine established cytogenetic risk groups