The β<sup>+</sup> IVS, I‐NT no. 6 (T→C) thalassaemia in heterozygotes with an associated Hb Valletta or Hb S heterozygosity in homozygotes from Malta

Scerri, Christian; Abela, W.; Galdies, Ruth; Pizzuto, Monica; Grech, Joseph; Felice, Alex E.

doi:10.1111/j.1365-2141.1993.tb04710.x

Cited by 20 publications

(6 citation statements)

References 8 publications

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“…Several founder effects have been reported on the island. 27,28 Given the high prevalence of diabetes in Malta, coupled to the reported differences in MODY across European latitudes and the high propensity for founder effects in a small island population, evaluating the molecular genetics of the disease is an important exercise with both clinical and public health implications.…”

Section: Discussionmentioning

confidence: 99%

Identification of an HNF1A p.Gly292fs Frameshift Mutation Presenting as Diabetes During Pregnancy in a Maltese Family

Pace

Rizzo

Abela

et al. 2019

Clin Med Insights Case Rep

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The diagnosis of maturity onset diabetes of the young (MODY) is a challenging process in view of the extensive clinical and genetic heterogeneity of the disease. Mutations in the gene encoding hepatocyte nuclear factor 1α ( HNF1A ) are responsible for most forms of monogenic diabetes in Northern European populations. Genetic analysis through a combination of whole exome sequencing and Sanger sequencing in three Maltese siblings and their father identified a rare duplication/frameshift mutation in exon 4 of HNF1A that lies within a known mutational hotspot in this gene. In this report, we provide the first description of an HNF1A -MODY3 phenotype in a Maltese family. The findings reported are relevant and new to a regional population, where the epidemiology of atypical diabetes has never been studied before. This report is of clinical interest as it highlights how monogenic diabetes can be misdiagnosed as either type 1, type 2, or gestational diabetes. It also reinforces the need for a better characterisation of monogenic diabetes in Mediterranean countries, particularly in island populations such as Malta with a high prevalence of diabetes.

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Section: Discussionmentioning

confidence: 99%

Identification of an HNF1A p.Gly292fs Frameshift Mutation Presenting as Diabetes During Pregnancy in a Maltese Family

Pace

Rizzo

Abela

et al. 2019

Clin Med Insights Case Rep

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“…The Hb epidemiology of Malta permits further exploration in vivo of the genetic interactions involved because it is characterized by the relatively high frequency of the Hb F variant, Hb F-Malta-I [ G γ117(G19)His→Arg, CAT→CGT] (12) and of the β + IVS-I-6 (T→C) thalassemia mutation (13).…”

Section: Introductionmentioning

confidence: 99%

A Review ofCis-TransInterplay Between DNA Sequences 5′ to the^Gγ- and β-Globin Genes Among Hb F-Malta-I Heterozygotes/Homozygotes and β-Thalassemia Homozygotes/Compound Heterozygotes, and the Effects of Hydroxyurea on the Hb F/F-Erythrocyte; the Need for Large Multicenter Trials

et al. 2007

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The biosynthesis of Hb F in place of the deficient Hb A could be a suitable treatment for beta hemoglobinopathies. Among newborn Hb F-Malta-I heterozygotes, it could be shown that the XmnI sequence alone had little, if any effect on gamma-globin gene expression, but interplay with the (AT)(X)T(Y) sites in cis and in trans may occur. In contrast, while the XmnI sequence is clearly correlated with gamma-globin levels in anemic adult beta-thalassemia (thal) homozygotes, the effect on F-erythrocyte numbers and Hb F/F-erythrocyte appears independent of the (AT)(X)T(Y) sites. Even at levels of hydroxyurea (HU) as low as 1.65 mg/kg/day (vs. 10 mg/kg/day on the high dose regime) it can be shown that although even a small increase of Hb F could be obtained, the effect was rarely translated into an increase in circulating hemoglobin (Hb). In most cases, the elevated Hb F level was dependent on the XmnI sequence and was due to increased numbers of F-erythrocytes or Hb F/F-erythrocyte or both. It seems that the bone marrow of thalassemia homozygotes may be more sensitive to myelosuppression by HU possibly due to medullary inflammation. While the data are consistent with loop models of globin switching mechanisms, there is urgent need for large, hypothesis driven, multicenter trials of molecules that could maintain or re-induce high Hb F levels in beta-thal and subject to genetic and epigenetic constraints including inflammation.

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“…Such studies may offer new insights into γ→β-globin gene switching and the change in G γ: A γ-globin ratio that accompanies it, and may be the basis of therapeutic approaches in the management of the hemoglobinopathies. β-Valletta with an associated β-thal mutation has also made possible the objective study of the effect of β-thal mutations on the expression of the β-globin gene in vivo (31,32). Hb F-Sardinia occurs at a frequency of 0.144 in Malta (27), and if found in conjunction with Hb F-Malta-I, would allow an even more objective study of allelic β-, G γ-and A γ-globin gene expression.…”

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confidence: 99%

Developmental Effect of theXmnI Site on^Gγ-Globin Gene Expression Among Newborn Hb F-Malta-I [^Gγ117(G19)His→Arg, CAT→CGT] Heterozygotes and Adult β⁺-Thalassemia Homozygotes

et al. 2007

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Hb F-Malta-I [Ggamma117(19)His-->Arg, CAT-->CGT] is a stable and benign variant of Hb F found in 1.8% of Maltese newborn. We studied 120 Hb F-Malta-I heterozygotes and four Hb F-Malta-I homozygotes. The mean proportion of Ggamma-F-Malta-I in Hb F was 0.26 +/- 0.03 for the Hb F-Malta-I heterozygotes and 0.58 +/- 0.06 for the Hb F-Malta-I homozygotes. The Hb F-Malta-I allele was shown to occur on a background of the common Mediterranean haplotype Va [+ + - - - - - + + -]. Furthermore, the common Mediterranean haplotypes Va, IIIb [- + + + - + + + + -], I [+ + - - - - - + + +] and II [- + - + + - + + + +] accounted for most (66.2%) of the wild-type alleles among the tested Hb F-Malta-I heterozygotes. Different genotypes at the 5' epsilon HincII, Ggamma and Agamma HindIII, and 3'psibeta HincII sites (but not at the 5' Ggamma XmnI site) were found to be linked to significant variations in the proportion of Ggamma-F-Malta-I and Ggamma-globins in the Hb F of newborn Hb F-Malta-I heterozygotes. Moreover, the 5' Ggamma XmnI site was found to be associated with variations in Hb F and Ggamma-globin levels in a population of adult Maltese beta-thalassemia (thal) homozygotes. This implies that a determinant linked to the XmnI site which effects Ggamma-globin gene expression is active in anemic adults but not in normal infants.

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The β⁺ IVS, I‐NT no. 6 (T→C) thalassaemia in heterozygotes with an associated Hb Valletta or Hb S heterozygosity in homozygotes from Malta

Cited by 20 publications

References 8 publications

Identification of an HNF1A p.Gly292fs Frameshift Mutation Presenting as Diabetes During Pregnancy in a Maltese Family

Identification of an HNF1A p.Gly292fs Frameshift Mutation Presenting as Diabetes During Pregnancy in a Maltese Family

A Review ofCis-TransInterplay Between DNA Sequences 5′ to the^Gγ- and β-Globin Genes Among Hb F-Malta-I Heterozygotes/Homozygotes and β-Thalassemia Homozygotes/Compound Heterozygotes, and the Effects of Hydroxyurea on the Hb F/F-Erythrocyte; the Need for Large Multicenter Trials

Developmental Effect of theXmnI Site on^Gγ-Globin Gene Expression Among Newborn Hb F-Malta-I [^Gγ117(G19)His→Arg, CAT→CGT] Heterozygotes and Adult β⁺-Thalassemia Homozygotes

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The β+ IVS, I‐NT no. 6 (T→C) thalassaemia in heterozygotes with an associated Hb Valletta or Hb S heterozygosity in homozygotes from Malta

Cited by 20 publications

References 8 publications

Identification of an HNF1A p.Gly292fs Frameshift Mutation Presenting as Diabetes During Pregnancy in a Maltese Family

Identification of an HNF1A p.Gly292fs Frameshift Mutation Presenting as Diabetes During Pregnancy in a Maltese Family

A Review ofCis-TransInterplay Between DNA Sequences 5′ to theGγ- and β-Globin Genes Among Hb F-Malta-I Heterozygotes/Homozygotes and β-Thalassemia Homozygotes/Compound Heterozygotes, and the Effects of Hydroxyurea on the Hb F/F-Erythrocyte; the Need for Large Multicenter Trials

Developmental Effect of theXmnI Site onGγ-Globin Gene Expression Among Newborn Hb F-Malta-I [Gγ117(G19)His→Arg, CAT→CGT] Heterozygotes and Adult β+-Thalassemia Homozygotes

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The β⁺ IVS, I‐NT no. 6 (T→C) thalassaemia in heterozygotes with an associated Hb Valletta or Hb S heterozygosity in homozygotes from Malta

A Review ofCis-TransInterplay Between DNA Sequences 5′ to the^Gγ- and β-Globin Genes Among Hb F-Malta-I Heterozygotes/Homozygotes and β-Thalassemia Homozygotes/Compound Heterozygotes, and the Effects of Hydroxyurea on the Hb F/F-Erythrocyte; the Need for Large Multicenter Trials

Developmental Effect of theXmnI Site on^Gγ-Globin Gene Expression Among Newborn Hb F-Malta-I [^Gγ117(G19)His→Arg, CAT→CGT] Heterozygotes and Adult β⁺-Thalassemia Homozygotes