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A de novo band 3 mutation in hereditary spherocytosis

To the Editor: Hereditary spherocytosis (HS) exhibits both dominant or nondominant inheritance. Dominant inheritance is associated with defects in ankyrin, beta spectrin, or band 3 while nondominant inheritance is associated with defects in alpha spectrin or protein 4.2, which are recessively inherited, or with de novo mutations [1]. Most de novo HS mutations have been found in the ankyrin or beta-spectrin genes, although a few have been described in the band 3 gene [1]. Identification of de novo mutations provides specific hematologic diagnosis and provides the necessary information for genetic counseling of affected individuals and families. We studied three generations of a family in which five of the seven children presented with HS. All five affected children had received transfusions within a 2-week period after parvovirus infection at ages 1, 5, 8, 13, and 18 years, respectively, following which four out of the five were splenectomized. Their father had HS and had been splenectomized in childhood. HS in this family was characterized by moderately compensated hemolytic anemia with reticulocytosis, elevated mean corpuscular hemoglobin concentration, and increased erythrocyte osmotic fragility after incubation. SDS–polyacrylamide gel electrophoresis of erythrocyte membrane proteins revealed a deficiency of band 3 protein between 35% and 40% in two affected individuals. Anion flux studies, measuring the transmembrane self-exchange flux of sulfate, performed on patient erythrocytes demonstrated a 40% decrease in self-exchange at all pHs tested compared to control. A heterozygous mutation in the band gene, c2423G > A, changing arginine to histidine at codon 808 was identified in the father and three of the five affected third generation children. DNA was not available for testing of the other two affected children. The mutation was not present in amplified genomic DNA from either of the father’s parents. Paternity of the grandfather/father pair was confirmed using a standard panel of markers, indicating that the R808H mutation was a de novo mutation in the father. HS-associated mutations of this codon have been described, including Arg808His and Arg808Cys [2–4]. Interestingly, the Arg808His mutation has been found in individuals of different ethnic backgrounds and once as a de novo mutation. HSassociated de novo mutations have primarily been associated with defects in the ankyrin and beta-spectrin genes. However, a few HS-associated de novo mutations in the band 3 gene have been described [2–6]. De novo mutations in band 3 associated with distal renal tubular acidosis and hereditary stomatocytosis associated with dyserythropoiesis have been described [7–9]. These data indicate that de novo mutations in the band 3 gene are found associated with human genetic disease more commonly than previously recognized. Data continue to accumulate indicating that the hereditary spherocytosis syndromes are frequently associated with de novo germ line mutations. This is similar to several other diseases such as neurofibromatosis 1 and hemophilia, where de novo mutations in very large genes are commonly observed, possibly influenced by the sequence context of these genes. Identification of de novo mutations provides specific hematologic diagnosis to affected individuals. It also provides the necessary information for genetic counseling of affected individuals and their family members.