Thiamine-responsive megaloblastic anemia: identification of novel compound heterozygotes and mutation update - PubMed (original) (raw)

. 2009 Dec;155(6):888-892.e1.

doi: 10.1016/j.jpeds.2009.06.017. Epub 2009 Jul 29.

Inderneel Sahai, Jill F Falcone, Judy Fleming, Adam Bagg, Caterina Borgna-Pignati, Robin Casey, Luca Fabris, Elizabeth Hexner, Lulu Mathews, Maria Leticia Ribeiro, Klaas J Wierenga, Ellis J Neufeld

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Thiamine-responsive megaloblastic anemia: identification of novel compound heterozygotes and mutation update

Anke K Bergmann et al. J Pediatr. 2009 Dec.

Abstract

Objective: To determine causative mutations and clinical status of 7 previously unreported kindreds with TRMA syndrome, (thiamine-responsive megaloblastic anemia, online Mendelian inheritance in man, no. 249270), a recessive disorder of thiamine transporter Slc19A2.

Study design: Genomic DNA was purified from blood, and SLC19A2 mutations were characterized by sequencing polymerase chain reaction-amplified coding regions and intron-exon boundaries of all probands. Compound heterozygotes were further analyzed by sequencing parents, or cloning patient genomic DNA, to ascertain that mutations were in trans.

Results: We detected 9 novel SLC19A2 mutations. Of these, 5 were missense, 3 were nonsense, and 1 was insertion. Five patients from 4 kindreds were compound heterozygotes, a finding not reported previously for this disorder, which has mostly been found in consanguineous kindreds.

Conclusion: SLC19A2 mutation sites in TRMA are heterogeneous; with no regional "hot spots." TRMA can be caused by heterozygous compound mutations; in these cases, the disorder is found in outbred populations. To the extent that heterozygous patients were ascertained at older ages, a plausible explanation is that if one or more allele(s) is not null, partial function might be preserved. Phenotypic variability may lead to underdiagnosis or diagnostic delay, as the average time between the onset of symptoms and diagnosis was 8 years in this cohort.

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Figures

Figure 1

Figure 1. Known Mutations in SLC19A2 Leading to TRMA

All 28 reported mutations are presented according to their location in the thiamine transporter gene SLC19A2. Squares represent the number of unique kindreds with such mutation.

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References

    1. Porter FS, Rogers LE, Sidbury JB., Jr Thiamine-responsive megaloblastic anemia. J Pediatr. 1969;74:494–504. - PubMed
    1. Neufeld EJ, Mandel H, Raz T, Szargel R, Yandava CN, Stagg A, et al. Localization of the gene for thiamine-responsive megaloblastic anemia syndrome, on the long arm of chromosome 1, by homozygosity mapping. Am J Hum Genet. 1997;61:1335–41. - PMC - PubMed
    1. Fleming JC, Tartaglini E, Steinkamp MP, Schorderet DF, Cohen N, Neufeld EJ. The gene mutated in thiamine-responsive anaemia with diabetes and deafness (TRMA) encodes a functional thiamine transporter. Nat Genet. 1999;22:305–8. - PubMed
    1. Raz T, Labay V, Baron D, Szargel R, Anbinder Y, Barrett T, et al. The spectrum of mutations, including four novel ones, in the thiamine-responsive megaloblastic anemia gene SLC19A2 of eight families. Hum Mutat. 2000;16:37–42. - PubMed
    1. Strom TM, Hortnagel K, Hofmann S, Gekeler F, Scharfe C, Rabl W, et al. Diabetes insipidus, diabetes mellitus, optic atrophy and deafness (DIDMOAD) caused by mutations in a novel gene (wolframin) coding for a predicted transmembrane protein. Hum Mol Genet. 1998;7:2021–8. - PubMed

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