Thiamine-responsive megaloblastic anemia, also known as 'TRMA' or 'Rogers syndrome,' is an early-onset autosomal recessive disorder defined by the occurrence of megaloblastic anemia, diabetes mellitus, and sensorineural deafness, responding in varying degrees to thiamine treatment. On the basis of a linkage analysis of affected families of Alaskan and of Italian origin, we found, using homozygosity mapping, that the TRMA-syndrome gene maps to a region on chromosome 1q23.2-23.3 (maximum LOD score of 3.7 for D1S1679). By use of additional consanguineous kindreds of Israeli-Arab origin, the putative disease-gene interval also has been confirmed and narrowed, suggesting genetic homogeneity. Linkage analysis generated the highest combined LOD-score value, 8.1 at a recombination fraction of 0, with marker D1S2799. Haplotype analysis and recombination events narrowed the TRMA locus to a 16-cM region between markers D1S194 and D1S2786. Several heterozygote parents had diabetes mellitus, deafness, or megaloblastic anemia, which raised the possibility that mutations at this locus predispose carriers in general to these manifestations. Characterization of the metabolic defect of TRMA may shed light on the role of thiamine deficiency in such common diseases.
Bibliographical noteFunding Information:
This work was supported by the Juvenile Diabetes Foundation International (support to N.C.) and, in part, by the Ministry of Sciences and Arts (Israel) (support to N.C.), the Ministry of Absorption (Israel) (support to N.C.), and the Joseph Alias Fund for Medical Research (support to H.M.). We thank the researchers of the Généthon laboratory, including Claire Rochette and Sylvie Lemarchand, for their assistance. Initial genomic screening was performed by the Marshfield Clinic, under a genotyping grant from the National Heart Lung and Blood Institute. We are grateful to Janae Donady, Lorie Smith, Carrie Adler, and Sheri Mezoff for genotyping assistance. E.J.N. is a fellow of the Lucille P. Markey Trust. C.N.Y. was supported by NIH grant HL075Z4 for this work. A grant from the Charles H. Hood Foundation (to E.J.N.) supported early portions of this work. The Alaskan kindred was diagnosed originally by Dr. Virginia Sybert, University of Washington, Seattle. We are indebted to Donna Fenske, M.S.N., M.P.H., Alaska Department of Health and Social Services, for calling the Alaskan kindred to our attention and to Dr. William Miner, Alaska Native Health Service. We are grateful to Prof. Borgna-Pignatti for supplying us with samples from kindred 2. The collaboration of the families is gratefully acknowledged.