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Localization of the congenital dyserythropoietic anemia II locus to chromosome 20q11.2 by genomewide search.

ABSTRACT: Congenital dyserythropoietic anemias (CDA) are genetic disorders characterized by anemia and ineffective erythropoiesis. Three main types of CDA have been distinguished: CDA I and CDA III, whose loci have been already mapped, and CDA II (MIM 224100), the most frequent among CDAs, which is transmitted as an autosomal recessive trait and is known also as "HEMPAS" (hereditary erythroblast multinuclearity with positive acidified serum). We have recruited a panel of well-characterized CDA II families and have used them to search for the CDA II gene by linkage analysis. After the exclusion of three candidate genes, we ob-tained conclusive evidence for linkage of CDA II to microsatellite markers on the long arm of chromosome 20 (20q11.2). A maximum two-point LOD score of 5.4 at a recombination fraction of .00 was obtained with marker D20S863. Strong evidence of allelic association with the disease was detected with the same marker. Some recombinational events established a maximum candidate interval of approximately 5 cM.

SUBMITTER: Gasparini P

PROVIDER: S-EPMC1716028 | biostudies-literature | 1997 Nov

REPOSITORIES: biostudies-literature

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Localization of the congenital dyserythropoietic anemia II locus to chromosome 20q11.2 by genomewide search.

Gasparini P P Miraglia del Giudice E E Delaunay J J Totaro A A Granatiero M M Melchionda S S Zelante L L Iolascon A A

American journal of human genetics 19971101 5

Congenital dyserythropoietic anemias (CDA) are genetic disorders characterized by anemia and ineffective erythropoiesis. Three main types of CDA have been distinguished: CDA I and CDA III, whose loci have been already mapped, and CDA II (MIM 224100), the most frequent among CDAs, which is transmitted as an autosomal recessive trait and is known also as "HEMPAS" (hereditary erythroblast multinuclearity with positive acidified serum). We have recruited a panel of well-characterized CDA II families ...[more]

PMID: 9345103

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Project description:BackgroundCongenital dyserythropoietic anemia type II (CDAII), the most common form of CDA, is an autosomal recessive condition. CDAII diagnosis is based on invasive, expensive, and time consuming tests that are available only in specialized laboratories. The recent identification of SEC23B mutations as the cause of CDAII opens new possibilities for the molecular diagnosis of the disease. The aim of this study was to characterize molecular genomic SEC23B defects in 16 unrelated patients affected by CDAII and correlate the identified genetic alterations with SEC23B transcript and protein levels in erythroid precursors.MethodsSEC23B was sequenced in 16 patients, their relatives and 100 control participants. SEC23B transcript level were studied by quantitative PCR (qPCR) in peripheral erythroid precursors and lymphocytes from the patients and healthy control participants. Sec23B protein content was analyzed by immunoblotting in samples of erythroblast cells from CDAII patients and healthy controls.ResultsAll of the investigated cases carried SEC23B mutations on both alleles, with the exception of two patients in which a single heterozygous mutation was found. We identified 15 different SEC23B mutations, of which four represent novel mutations: p.Gln214Stop, p.Thr485Ala, p.Val637Gly, and p.Ser727Phe. The CDAII patients exhibited a 40-60% decrease of SEC23B mRNA levels in erythroid precursors when compared with the corresponding cell type from healthy participants. The largest decrease was observed in compound heterozygote patients with missense/nonsense mutations. In three patients, Sec23B protein levels were evaluated in erythroid precursors and found to be strictly correlated with the reduction observed at the transcript level. We also demonstrate that Sec23B mRNA expression levels in lymphocytes and erythroblasts are similar.ConclusionsIn this study, we identified four novel SEC23B mutations associated with CDAII disease. We also demonstrate that the genetic alteration results in a significant decrease of SEC23B transcript in erythroid precursors. Similar down-regulation was observed in peripheral lymphocytes, suggesting that the use of these cells might be sufficient in the identification of Sec23B gene alterations. Finally, we demonstrate that decreased Sec23B protein levels in erythroid precursors correlate with down-regulation of the SEC23B mRNA transcript.

Dataset Information

Localization of the congenital dyserythropoietic anemia II locus to chromosome 20q11.2 by genomewide search.

Publications

Localization of the congenital dyserythropoietic anemia II locus to chromosome 20q11.2 by genomewide search.

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