Different impacts of alleles α^LEPRA and α^LELY as assessed versus a novel, virtually null allele of the SPTA1 gene in trans

Abstract

Different impacts of alleles aLEPRA and a LELY as assessed versus a novel, virtually null allele of the SPTA1 gene in trans A subset of hereditary spherocytosis (HS) is associated with a reduction in red cell membrane spectrin (Agre et al, 1985). The SPTA1 gene, related to recessively inherited spherocytosis belongs to this subset. It is characterized by a pronounced and isolated decrease in spectrin. Under normal conditions, there is an overproduction of spectrin a-chains, however its extent has not been accurately assessed in humans. Wichterle et al (1996) elucidated the first mutations in a compound heterozygote. One mutation was null (mutation Prague). The other was polymorphic allele a LEPRA , carrying a c fi t transition at position )99 of intron 30, or mutation a LEPRA . An acceptor splice site at position )70 of intron 30 was activated, generating a frameshift. However, 16% of the transcripts escaped the abnormal splicing and allowed low a-chain production from allele a LEPRA (Wichterle et al, 1996). Allele a LEPRA accounts for nearly 5% of SPTA1 alleles among white people (Wichterle et al, 1996).Polymorphic allele a LELY is another low expression, more frequent, allele of the SPTA1 gene known to be involved with hereditary elliptocytosis (HE) (Alloisio et al, 1991;Wilmotte et al, 1993). A c fi t substitution at position )12 of intron 45 caused exon 46 (18 bp) to be skipped in 50% of the transcripts. The a-chains missing the corresponding 6 amino-acids were unsuitable for dimerisation (Wilmotte et al, 1997). The unaffected half of the transcripts ensured a 50% production from allele a LELY . The haploid set of a-chains in trans, carrying the HE mutation at or near the tetramerisation site, took over. More ab HE dimers than normal ab dimers were formed. The tetramerisation defect was enhanced and HE was aggravated. An effect of allele a LELY on the HS alleles of the SPTA1 gene has never been documented. Allele a LELY accounts for 20-30% of SPTA1 alleles, in all ethnic groups studied thus far (Maréchal et al, 1995;Basseres et al, 1998 Généthon,

Abnormalities of the Erythrocyte Membrane

“…A subset of patients presents with severe anemia in utero or immediately after birth and require red blood cell transfusion. 17-19 These patients frequently remain transfusion dependent and suffer from severe HS.…”

Molecular Genetic Mechanisms of Hereditary Spherocytosis: Current Perspectives

“…Delaunay et al [34] identified compound heterozygous mutations in 2 alleles in a family in which the siblings had severe HS, αLEPRA (from the mother), and αLELY-Bicêtre (from the father; resulting in G→A at position 2377 in exon 51 of the lowly expressed polymor phic allele, αLELY, essentially a null mutation of a synthetic nonfunctional protein). The α-chain yield of αLEPRA and αLELY-Bicêtre is 16 and 0% of the normal amount, respectively.…”

Large deletions of the 5′ region of IKZF1 lead to haploinsufficiency in B‐cell precursor acute lymphoblastic leukaemia

“…SPTA1 aLELY (SPTA1 IVS45-12C>T), a common low-expression allele (Delaunay et al, 2004) was investigated. The proband harboured heterozygous aLELY inherited from his father, while it was absent from his mother and grandfather.…”

“…These findings partially explained the variable expression between the proband and his mother. Delaunay et al (2004) reported that SPTA1 aLELY is adequately strong and may play no role in SPTA1-related HS. Herein, we found that SPTA1 aLELY may modify the phenotype of HE.…”