Molecular characterization of beta-thalassemia intermedia in patients of Italian descent and identification of three novel beta-thalassemia mutations

Murru, S; Loudianos, Georgios; Deiana, Manila; Camaschella, Clara; Sciarratta, G. V.; Agosti, Steven J.; Parodi, MI; P, Cerruti; Cao, Antonio; Pirastu, Mario

doi:10.1182/blood.v77.6.1342.1342

Cited by 63 publications

(19 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…¹158 G g-T was also common whereas athalasaemia was rare (Table III). This genotypic spectrum of TI is similar to that in mainland Italy, Turkey, China and Greece (Antonarakis et al, 1988;Gurgey et al, 1989;Murru et al, 1991;Camaschella et al, 1995;Kanavakis et al, 1995), in contrast to India, where ¹158 G g-T (Thein et al, 1988), and Sardinia, where ¹158 G g-T and homozygous a þthalasaemia predominate (Galanello et al, 1989).…”

Section: Discussionsupporting

confidence: 63%

Beta‐thalassaemia in the immigrant and non‐immigrant German populations

et al. 1997

View full text Add to dashboard Cite

Summary.In Germany homozygous b-thalassaemia mainly occurs in the immigrant population from endemic regions. In non-immigrants b-thalassaemia is rare. Heterozygous b-thalassaemia minor, however, is more common and must be considered in the differential diagnosis of hypochromic anaemia. The clinical and molecular data of 221 homozygous patients and 256 non-immigrant German heterozygous individuals are presented. Clinically, 87% (n ¼ 192) of the homozygotes are classified as thalassaemia major (TM) and the other 13% as thalassaemia intermedia (TI). There is a wide spectrum of 39 thalassaemia mutations which occur with relatively low frequencies in individual cases. In 17/29 TI patients 'mild' mutations have been found and in 16/29 there are mutations that are associated with increased g-globin gene activity. a-Thalassaemia is rare and found only in 3/29.In the 256 Germans with heterozygous b-thalassaemia there are 27 different thalassaemia mutations. The three most common are Mediterranean, together accounting for 61%. Also relatively common (5%) is an otherwise rare frameshift mutation of codon 83 (FS83 DG). The other mutations occur in < 10 individuals. Two mutations described here are novel. One of them affects position ¹2 of the intron 1 splice acceptor site (IVSI-129 A-G) and the other is a deletion of a single G in codon 15/16 (FS 15/16 DG). These data suggest that b-thalassaemia in Germans was introduced from the Mediterranean in about two-thirds of cases and that the remaining third has probably originated locally.

show abstract

Section: Discussionsupporting

confidence: 63%

Beta‐thalassaemia in the immigrant and non‐immigrant German populations

et al. 1997

View full text Add to dashboard Cite

show abstract

“…The py tract is probably involved in determining the splicing preference in case of alternative splicing (Libri et al , 1992; Guo & Helfman, 1993). Six transversions in the py tract have been shown to affect splicing (Sebillon et al , 1995; Huie et al , 1994; Higashi et al , 1988; Murru et al , 1991; Tee et al , 1995; Fournier et al , 1997). In allele α LELY not only does intron 45 mutation represent an example of a simple pyrimidine to pyrimidine substitution in a py tract that modulates the skipping of an exon, but also an example in which the skipping is partial.…”

Section: Discussionmentioning

confidence: 99%

Mutation at position −12 of intron 45 (c → t) plays a prevalent role in the partial skipping of exon 46 from the transcript of allele α^LELY in erythroid cells

1999

View full text Add to dashboard Cite

Summary. Allele aLELY is a common low-expression allele of the erythroid spectrin SPTA1 gene. It results in the aggravated expression of hereditary elliptocytosis due to SPTA1 gene mutations occurring in trans. Allele a LELY contains, in particular, mutations in introns 45 and 46, both in polypyrimidine tracts, and causes the partial skipping of exon 46. The corresponding six amino acids belong to the nucleation site where the dimerization process of spectrin begins. In this work we investigated the cause of exon 46 partial skipping. We made four types of constructs with or without the intron 45 mutation, and with or without intron 46 mutation. Intron 45 mutation by itself dramatically triggered partial skipping of exon 46. Intron 46 mutation had no effect by itself. It was not possible to assess whether it modulated, even to a very small extent, the activity of intron 45 mutation. Taken together, intron 45 mutation is the prevalent, if not the exclusive, determinant of the partial skipping of exon 46 in the transcript of allele a Hereditary elliptocytosis (HE) is often caused by abnormal alleles (a HE alleles) of the SPTA1 gene which encodes the erythroid spectrin a-chain. In virtually all families carrying a HE alleles, mild or even symptomless individuals, and more severely affected persons, have been observed. Linkage studies (Guetarni et al, 1990), spectrin maps (Alloisio et al, 1991) and SPTA1 gene analysis (Wilmotte et al, 1993) have defined a common low-expression allele, or allele a LELY , which accounted for the aggravated expression of HE when occurring in trans of the a HE allele. Allele a LELY carries three alterations: a point mutation in exon 40 (L 1857 V; CTA → GTA), thought to be a neutral polymorphism, a point mutation in intron 45 (6714; ¹12 c → t) and still another mutation in intron 46 (6732; ¹12 g → a). These three mutations are in 100% linkage desequilibrium, although intron 46 mutation is also found in some nona LELY alleles. Half of the a LELY transcripts undergo a partial skipping of exon 46 (Wilmotte et al, 1993).The formation of spectrin ab heterodimers starts at two nucleation sites. One is on the a-chain: repeating segments a18-21 (Speicher et al, 1992), and contains exon 46 encoded six amino acids. Another is on the b-chain (Ursitti et al, 1996). The deleterious effect of allele a LELY stems from the absence exon 46-encoded amino acids (Wilmotte et al, 1997). When an a HE allele occurs in trans, the a HE chains are preferably recruited. An increased proportion of the a HE b-dimers enhances the self-association defect generated by the a HE mutation and eventually worsens the clinical presentation.We assumed that the intron 45 mutation triggered the partial skipping of exon 46 from a LELY transcripts, although it did not appear to be a good candidate, being a pyrimidine to pyrimidine transition within the pyrimidine-rich region. Based on transfection experiments, we showed that intron 45 mutation played a prevalent, if not an exclusive, role in the partial skipping of exon 46. METHOD...

show abstract

“…The CrG change at position Ϫ5 does change a pyrimidine to a purine in the consensual polypyrimidine track. Such polypyrimidine-track mutations have been described in the b-globin gene (Beldjord et al 1998;Murru et al 1991), the ATR-X gene (Villard et al 1996), and the steroidogenic acuteregulatory-protein gene (Tee et al 1995).…”

Section: Figurementioning

confidence: 99%

X-Linked Dyskeratosis Congenita Is Predominantly Caused by Missense Mutations in the DKC1 Gene

Knight

Heiss

Vulliamy

et al. 1999

The American Journal of Human Genetics

224

168

View full text Add to dashboard Cite

Dyskeratosis congenita is a rare inherited bone marrow-failure syndrome characterized by abnormal skin pigmentation, nail dystrophy, and mucosal leukoplakia. More than 80% of patients develop bone-marrow failure, and this is the major cause of premature death. The X-linked form of the disease (MIM 305000) has been shown to be caused by mutations in the DKC1 gene. The gene encodes a 514-amino-acid protein, dyskerin, that is homologous to Saccharomyces cerevisiae Cbf5p and rat Nap57 proteins. By analogy to the homologues in other species, dyskerin is predicted to be a nucleolar protein with a role in both the biogenesis of ribosomes and, in particular, the pseudouridylation of rRNA precursors. We have determined the genomic structure of the DKC1 gene; it consists of 15 exons spanning a region of 15 kb. This has enabled us to screen for mutations in the genomic DNA, by using SSCP analysis. Mutations were detected in 21 of 37 additional families with dyskeratosis congenita that were analyzed. These mutations consisted of 11 different single-nucleotide substitutions, which resulted in 10 missense mutations and 1 putative splicing mutation within an intron. The missense change A353V was observed in 10 different families and was shown to be a recurring de novo event. Two polymorphisms were also detected, one of which resulted in the insertion of an additional lysine in the carboxy-terminal polylysine domain. It is apparent that X-linked dyskeratosis congenita is predominantly caused by missense mutations; the precise effect on the function of dyskerin remains to be determined.

show abstract

Molecular characterization of beta-thalassemia intermedia in patients of Italian descent and identification of three novel beta-thalassemia mutations

Cited by 63 publications

References 16 publications

Beta‐thalassaemia in the immigrant and non‐immigrant German populations

Beta‐thalassaemia in the immigrant and non‐immigrant German populations

Mutation at position −12 of intron 45 (c → t) plays a prevalent role in the partial skipping of exon 46 from the transcript of allele α^LELY in erythroid cells

X-Linked Dyskeratosis Congenita Is Predominantly Caused by Missense Mutations in the DKC1 Gene

Contact Info

Product

Resources

About

Molecular characterization of beta-thalassemia intermedia in patients of Italian descent and identification of three novel beta-thalassemia mutations

Cited by 63 publications

References 16 publications

Beta‐thalassaemia in the immigrant and non‐immigrant German populations

Beta‐thalassaemia in the immigrant and non‐immigrant German populations

Mutation at position −12 of intron 45 (c → t) plays a prevalent role in the partial skipping of exon 46 from the transcript of allele αLELY in erythroid cells

X-Linked Dyskeratosis Congenita Is Predominantly Caused by Missense Mutations in the DKC1 Gene

Contact Info

Product

Resources

About

Mutation at position −12 of intron 45 (c → t) plays a prevalent role in the partial skipping of exon 46 from the transcript of allele α^LELY in erythroid cells