β‐Spectrin S^ta Bárbara: a novel frameshift mutation in hereditary spherocytosis associated with detectable levels of mRNA and a germ cell line mosaicism

Abstract

Hereditary spherocytosis (HS) is a common inherited anaemia characterized by the presence of spherocytic red cells and by a heterogeneous nature in terms of its clinical presentation, molecular basis and inheritance. Defects in several membrane protein genes have been involved in the pathogenesis of HS, including defects in the beta-spectrin gene. We detected a novel frameshift mutation in the beta-spectrin gene, a C deletion at codon 638, in a patient presenting with HS and spectrin deficiency. The mutant protein was not detected in the membrane or in other cellular compartments, but detectable levels of mutant mRNA were found in the patient. Interestingly, this mutation was not present in the patient's parents, suggesting a genetic mosaicism, especially as the patient has an affected brother with the same molecular defect. We analysed DNA from different tissues of the parents and the mutation was absent from all tissues analysed. This mutation seems to be confined to the germ cell lineage of the patient's mother and must present a mosaic pattern in these cells as the patient also has unaffected siblings.

Novel beta‐spectrin mutations in hereditary spherocytosis associated with decreased levels of mRNA

“…On the other hand, it cannot be excluded that the truncated protein is degraded or its membrane incorporation is disturbed; in this case, only the normal, full‐length protein would be present in the cell membrane. This kind of situation was reported by Bassères et al (2001) who found that, in an HS subject with detectable levels of SPTB mRNA bearing a premature STOP codon, the mutant protein was undetectable in the erythrocyte membrane.…”

“…The G1408R substitution was first reported by Bassères et al (2001). Since the predicted glycine‐to‐arginine change could potentially be severe, we initially speculated that this genetic change might be responsible for spherocytosis.…”

Mutational characteristics of ANK1 and SPTB genes in hereditary spherocytosis

“…After a literature search related to HS, 50 cases including 31 ANK1 and 19 SPTB mutations were identified. These reports provided laboratory and clinical data, such as Hb level, splenectomy, and aplastic crisis which allowed calculation of the difference of Hb level according to mutated genes or the frequencies of splenectomy and aplastic crisis according to located domain of mutation in each gene.…”

Novel hereditary spherocytosis-associated splice site mutation in the ANK1 gene caused by parental gonosomal mosaicism

“…Bassères DS et al reported a de novo frameshift mutation in the SPTB gene, and they supposed that the mutation might be caused by parental germline mosaicism without further confirmation. 15 In conclusion, mosaicisms pose challenging dilemmas for the diagnosis, prognosis and reproductive counseling of families with individuals affected by mosaic diseases. When parents have a child with constitutional, de novo occurrence of a disorder inherited in autosomal dominant pattern, parental germline or gonosomal mosaicisms must be considered, and they are at risk of passing on the same mutation to future children.…”