: Thiamine‐responsive megaloblastic anaemia (TRMA) is a rare autosomal recessive condition, characterized by megaloblastic anaemia, non‐autoimmune diabetes mellitus, and sensorineural hearing loss. ...We describe three infants with TRMA from two consanguineous Pakistani families, who were not known to be related but originated from the same area in Pakistan. All children were homozygous, and the parents were heterozygous for a c.196G>T mutation in the SLC19A2 gene on chromosome 1q23.3, which encodes a high‐affinity thiamine transporter. The result is an abnormal thiamine transportation and vitamin deficiency in the cells. Thiamine in high doses (100–200 mg/d) reversed the anaemia in all our patients. Two patients discontinued insulin treatment successfully after a short period, while the third patient had to continue with insulin. The hearing loss persisted in all three children. The diagnosis of TRMA should be suspected in patients with syndromic diabetes including hearing loss and anaemia, even if the latter is only very mild and, particularly, in the case of consanguinity.
The micronutrient thiamine is required for normal growth and development of human tissues, and is accumulated into cells through the activity of plasma membrane thiamine transporters, e.g. hTHTR1 ...(human thiamine transporter 1). Recent genetic evidence has linked mutations in hTHTR1 with the manifestation of TRMA (thiamine-responsive megaloblastic anaemia), a condition also associated with diabetes mellitus, sensorineural deafness and retinal disorders. To examine how mutations in hTHTR1 impair thiamine accumulation, we have investigated the targeting and functional properties of several different hTHTR1 mutants in human cell lines derived from epithelia relevant to thiamine absorption or tissues implicated in TRMA pathology. These constructs encompassed two newly identified point mutations (P51L and T158R) and two truncations of hTHTR1 identical with those found in TRMA kindreds (W358X and Delta383fs). Our results reveal a spectrum of mutant phenotypes, underlining that TRMA can result from decreased thiamine transport activity underpinned by changes in hTHTR1 expression levels, cellular targeting and/or protein transport activity.
Thiamine responsive megaloblastic anemia syndrome (TRMA), an autosomal recessive disorder caused by the deficiency of thiamine transporter protein, is the association of diabetes mellitus, anemia and ...deafness. Pharmacological dose thiamine normalizes hematological abnormalities and their effects on the course of diabetes mellitus. We report on 8 years follow up of two siblings with TRMA. They presented in the prepubertal period with diabetic ketoacidosis due to lack of thiamine supplementation for 2 months. Their insulin requirements fell rapidly and disappeared with thiamine therapy. Hematological parameters normalized within 30 days. The diabetic picture is responsive to thiamine treatment in patients with TRMA. Insulin dependent diabetes may occur throughout the pubertal period. If thiamine supplementation is not sufficient, ketoacidosis may develop in patients during the prepubertal period.
Over the past 30 years it has become apparent that not all diabetes presenting in childhood is autoimmune type 1. Increasingly type 2 diabetes, maturity onset diabetes of the young, iatrogenic ...diabetes, and rare syndromic forms of diabetes such as Wolfram’s syndrome have been identified in children. This review is aimed at the general paediatrician looking after children with diabetes, and aims to provide an algorithm for assessment, investigation, and suggested management for the newly diagnosed child with suspected non-type 1 diabetes. This article will also be relevant to the child with atypical diabetes—that is, on low insulin doses outside the honeymoon period.
The thiamine transporter geneSLC19A2 was recently found to be mutated in thiamine responsive megaloblastic anaemia with diabetes and deafness (TRMA, Rogers syndrome), an early onset autosomal ...recessive disorder. We now report a novel G1074A transition mutation in exon 4 of theSLC19A2 gene, predicting a Trp358 to ter change, in a girl with consanguineous parents. In addition to the typical triad of Rogers syndrome, the girl presented with short stature, hepatosplenomegaly, retinal degeneration, and a brain MRI lesion. Both muscle and skin biopsies were obtained before high dose thiamine supplementation. While no mitochondrial abnormalities were seen on morphological examination of muscle, biochemical analysis showed a severe deficiency of pyruvate dehydrogenase and complex I of the respiratory chain. In the patient's fibroblasts, the supplementation with high doses of thiamine resulted in restoration of complex I activity. In conclusion, we provide evidence that thiamine deficiency affects complex I activity. The clinical features of TRMA, resembling in part those found in typical mitochondrial disorders with complex I deficiency, may be caused by a secondary defect in mitochondrial energy production.
Exposure of cells to elevated temperatures triggers the synthesis of chaperones and proteases including components of the conserved Clp protease complex. We demonstrated previously that the ...proteolytic subunit, ClpP, plays a major role in stress tolerance and in the degradation of non‐native proteins in the Gram‐positive bacterium Lactococcus lactis. Here, we used transposon mutagenesis to generate mutants in which the temperature‐ and puromycin‐sensitive phenotype of a lactococcal clpP null mutant was partly alleviated. In all mutants obtained, the transposon was inserted in the L. lactis trmA gene. When analysing a clpP, trmA double mutant, we found that the expression normally induced from the clpP and dnaK promoters in the clpP mutant was reduced to wild‐type level upon introduction of the trmA disruption. Additionally, the degradation of puromycyl‐containing polypeptides was increased, suggesting that inactivation of trmA compensates for the absence of ClpP by stimulating an as yet unidentified protease that degrades misfolded proteins. When trmA was disrupted in wild‐type cells, both stress tolerance and proteolysis of puromycyl peptides was enhanced above wild‐type level. Based on our results, we propose that TrmA, which is well conserved in several Gram‐positive bacteria, affects the degradation of non‐native proteins and thereby controls stress tolerance.
Thiamine-responsive megaloblastic anemia with diabetes and deafness (TRMA) is an autosomal recessive disease caused by mutations in the high-affinity thiamine transporter gene
SLC19A2. To study the ...role of thiamine transport in the pathophysiology of TRMA syndrome and of each of the component disorders, we created a targeted disruption of the
Slc19a2 gene in mice.
Slc19a2 −/− mice are viable and females are fertile. Male −/− mice on a pure 129/Sv background are infertile with small testes (testis/body weight=0.13
±
0.04 knockout vs. 0.35
±
0.05 wild type,
P<0.000005). The lack of developing germ cells beyond primary spermatocytes suggests an arrest in spermatogenesis prior to meiosis II. Nuclear chromatin changes indicative of apoptosis are present. No mature sperm are found in the tubules or epididymis. This phenotype suggests a previously unknown role for thiamine transport in spermatogenesis and male fertility.
Slc19a2 −/− mice on a pure 129/Sv background develop reticulocytopenia after two weeks on thiamine-depleted chow with a virtual absence of reticulocytes in the peripheral blood (0.12% knockout vs. 2.58% wild type,
P=0.0079). Few erythroid precursors are found in the bone marrow. Contrary to human TRMA syndrome, we see no evidence of megaloblastosis or ringed sideroblasts in the bone marrow of
Slc19a2 −/− mice in thiamine-replete or thiamine-deficient dietary states. Phenotypic differences between TRMA patients and
Slc19a2 −/− mice might be explained by dissimilar tissue expression patterns of the transporter, as well as by differing metabolic needs and possible different species-specific contributions of the related thiamine transporter Slc19a3.
Formylation of initiator methionyl-tRNA is essential for normal growth of eubacteria. However, under special conditions, it has been possible to initiate protein synthesis with unformylated initiator ...tRNA even in eubacteria. Earlier studies suggested that the lack of ribothymidine (rT) modification in initiator tRNA may facilitate initiation in the absence of formylation. In this report we show, by using trmA strains of Escherichia coli (defective for rT modification) and a sensitive in vivo initiation assay system, that the lack of rT modification in the initiators is not sufficient to effect formylation-independent initiation of protein synthesis.
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