Frequent de novo monoallelic expression of β‐spectrin gene (SPTB) in children with hereditary spherocytosis and isolated spectrin deficiency

Abstract

This report represents an attempt to define the rate of beta-spectrin de novo mutations affecting mRNA accumulation in patients with hereditary spherocytosis (HS). 19 HS children with haematologically normal parents and varying degrees of spectrin deficiency were studied. 13 of the 19 cases who were heterozygous at the genomic level for polymorphisms in the beta-spectrin coding region were further studied. However, in an analysis of reverse-transcripted amplified cDNA from the regions of the polymorphisms, seven patients appeared to be homozygous, suggesting the occurrence of de novo mutational events affecting expression of one beta-spectrin allele. We conclude that in HS patients with isolated spectrin reduction and normal parents the apparently recessive pattern of inheritance may frequently be associated with de novo monoallelic expression of beta-spectrin.

An acquired G-CSF receptor mutation results in increased proliferation of CMML cells from a patient with severe congenital neutropenia

“…25 Recently, a patient with juvenile myelomonocytic leukemia was reported with both an oncogenic mutation in the PTPN11 gene and loss of the normal allele. 26 Monoallelic expression of a de novo mutated gene has been described earlier, 27 and seems to be a common feature for the expression of the tumor suppressor gene p73 in de novo AML. 28 Our data are compatible with either somatic deletion of the normal G-CSFR allele in a subset of circulating CMML MNCs or with epigenetic inactivation of the normal allele.…”

Lack of F8 mRNA: a novel mechanism leading to hemophilia A

“…17 In addition to these genes, pathologic monoallelic expression in disease-related genes were also reported. [18][19][20] For example, congenital hypothyroidism is a recessive disease caused by mutations in thyroid peroxidase (TPO); patients are usually homozygous or compound heterozygous for gene mutations. In some 17% of the cases there is only one mutated allele; in one of these cases Fugazzola et al 18 showed that the intact allele on the DNA level is unexpressed and undetectable on the RNA level.…”

Simultaneous (AC)n microsatellite polymorphism analysis and single‐stranded conformation polymorphism screening is an efficient strategy for detecting ankyrin‐1 mutations in dominant hereditary spherocytosis

“…If characterization of the underlying mutation is desirable, we propose that, initially, genomic DNA and reticulocyte RNA should be compared for the reduced expression of one cDNA allele using the (AC) n repeat (Jarolim et al, 1995;Randon et al, 1997;Miraglia del Giudice et al, 1998b) and/or other ANK1 polymorphisms, and to proceed with SSCP screening of all ANK1 exons only in patients who show the absence of one ankyrin allele in the reticulocyte RNA. In families that do not show a reduced expression of one ankyrin cDNA allele, we recommend comparing genomic DNA and mRNA (as cDNA) for a reduced expression of one cDNA allele using frequent polymorphisms of other frequently affected genes in HS such as band 3 (Eber et al, 1996;Jarolim et al, 1992Jarolim et al, , 1997 or b-spectrin I (Hassoun et al, 1997;Dhermy et al, 1998;Miraglia del Giudice et al, 1998a). Exon 3, codon 61 (GTG fi GTC, silent) 267 G fi C 1( 0 AE02) 0 (0AE00) Exon 7, codon 218 (AAC fi AAA, Asn fi Lys) N218K 1 (0AE02) 1 (0AE01) Exon 36, codon 1455 (GTC fi GTT, silent) 4469 C fi T 1( 0 AE02) 0 (0AE00) Exon 36, codon 1462 (GCA fi GTA, Ala fi Val) A1462V 2 (0AE05) 1 (0AE03) Exon 38, codon 1658 (GAC fi GAT, silent) 5058 C fi T 1( 0 AE02) 1 (0AE01)…”

“…Primary molecular defects are found in the red blood cell (RBC) membrane proteins spectrin a (Wichterle et al, 1996), spectrin b (Hassoun et al, 1997;Dhermy et al, 1998;Miraglia del Giudice et al, 1998a), ankyrin-1 (Eber et al, 1996), band 3 (AE1, anion exchanger 1) and protein 4AE2 (Bouhassira et al, 1992). Approximately two-thirds of patients have combined spectrin and ankyrin-1 deficiency (Pekrun et al, 1993;Savvides et al, 1993).…”