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11/74. Elliptocytosis associated with an abnormal alpha glycophorin.

    A case of elliptocytosis associated with an undescribed abnormal alpha glycophorin (alpha GP) is reported. Using immunoblotting techniques, a clear-cut minor band 6' was detected emerging just behind the monomer of delta GP (band 6) when probed with anti-alpha GP antiserum. It also reacted with anti-peptide C antiserum, suggesting that this new band with a molecular weight of 24 K is related to the structural alteration of alpha GP and not delta GP. The erythrocyte membrane proteins of the patient exhibited a quite normal pattern, with a normal alpha spectrin/beta spectrin ratio, but the reaction with anti-protein 4.1 serum confirmed the increase in proteolytic susceptibility of her protein 4.1. The results of dna mapping implied that the abnormality may be due to a short deletion of the heterozygote. The significance of deviation involving the alpha GP and protein 4.1 to the elliptocytic change of erythrocyte shape is briefly discussed. ( info)

12/74. Novel compound heterozygous SLC4A1 mutations in Thai patients with autosomal recessive distal renal tubular acidosis.

    BACKGROUND: Mutations in the SLC4A1 gene have been found to cause either autosomal dominant (AD) or autosomal recessive (AR) distal renal tubular acidosis (dRTA). The SLC4A1 mutations causing AD dRTA were reported in white patients, whereas those associated with AR dRTA were often found in Southeast asia. Here, the authors report additional novel SLC4A1 mutations in 3 patients with AR dRTA from 2 unrelated Thai families. methods: The patients and members of their families were clinically studied. Red cell morphology and sulfate influx were examined. The SLC4A1 gene was screened, analyzed, and confirmed for mutations by molecular genetic techniques. RESULTS: In the first family, the patient had dRTA, rickets, failure to thrive, nephrocalcinosis, and hypokalemic-hyperchloremic metabolic acidosis with a urine pH level of 7.00. He had novel compound heterozygous SLC4A1 G701D/S773P mutations, inherited from clinically normal heterozygous mother and father. In the second family, the patient and his sister had dRTA and Southeast Asian ovalocytosis (SAO) with different clinical severity. The patient had proximal muscle weakness, rickets, nephrocalcinosis, hypokalemia, normal anion gap metabolic acidosis, and urine pH level of 6.80. His sister was asymptomatic but the urine pH level could not be lowered to below 5.50 after a short acid load. Both siblings had compound heterozygous SLC4A1 SAO/R602H mutations. CONCLUSION: Two novel compound heterozygous SLC4A1 G701D/S773P and SAO/R602H mutations were identified in Thai patients with AR dRTA. ( info)

13/74. Basis of unique red cell membrane properties in hereditary ovalocytosis.

    Hereditary ovalocytes from a Mauritian subject are extremely rigid, with a shear elastic modulus about three times that of normal cells, and have increased resistance to invasion by the malaria parasite plasmodium falciparum in vitro. The genetic anomaly resides in band 3; the protein gives rise to chymotryptic fragments with reduced mobility in SDS/polyacrylamide gel electrophoresis, but this is a result of anomalous binding of SDS and not a higher molecular weight. Analysis of the band 3 gene reveals (1) a point mutation (Lys56   Glu), which also occurs in a common asymptomatic band 3 (Memphis) variant and governs the electrophoretic properties, and (2) a deletion of nine amino acid residues, including a proline residue, encompassing the interface between the membrane-associated and the N-terminal cytoplasmic domains. The interaction of the mutant band 3 with ankyrin appears unperturbed. The fraction of band 3 capable of undergoing translation diffusion in the membrane is greatly reduced in the ovalocytes. cells containing the asymptomatic band 3 variant were normal with respect to all the properties that we have studied. Possible mechanisms by which a structural change in band 3 at the membrane interface could regulate rigidity are examined. ( info)

14/74. Elliptocytosis-associated spectrin Rouen (beta 220/218) has a truncated but still phosphorylatable beta chain.

    spectrin Rouen (beta 220/218) is a novel variant, carrying a shortened beta chain with an apparent molecular weight of 218 kDa. It was detected in a French family. All affected members suffered from haemolytic hereditary elliptocytosis. As other shortened beta chain variants described before, the beta Rouen chain is truncated at its carboxyl terminus. spectrin Rouen is associated with a defect in spectrin dimer self-association and with an abnormally high amount of the alpha I 74 kDa peptide following partial tryptic digestion. Dimer reconstitution experiments from normal and abnormal purified Sp subunits indicated that the increased alpha I 74 kDa fragment is induced by the altered beta chain. However, spectrin Rouen is different from other mutants with a truncated beta chain in several respects: its amount is low (less than 10%) and the spectrin dimer self-associated defect is mild. Critically, the beta Rouen chain has retained the ability of undergoing phosphorylation, even though it is modified in its C-terminal region. These results, compared to those obtained with beta 220/214 spectrin Le Puy and beta 220/216 spectrin Nice, allowed better localization of the beta chain sites that can be phosphorylated by a membrane-bound casein kinase. ( info)

15/74. Elliptocytogenic alpha I/36 spectrin Sfax lacks nine amino acids in helix 3 of repeat 4. Evidence for the activation of a cryptic 5'-splice site in exon 8 of spectrin alpha-gene.

    Elliptocytogenic alpha I/36 spectrin Sfax is a new variant found in a Tunisian family. The alpha I/36 allele yielded a clinically manifest picture only when occurring in trans to a recently identified, low expression level polymorphism referred to as the alpha V/41 allele. spectrin dimers were slightly increased in 4 degrees C extracts. On peptide maps, the alpha I domain split into two abnormal fragments of 36 and 33 Kd. The mutated alpha-chain represented 20% and 44% of total alpha-chain in alpha/alpha I/36 and alpha V/41/alpha I/36 heterozygotes, respectively. Peptide sequencing showed that the 36-Kd fragment started at Ala 357 and displayed a deletion extending from amino acids 363 to 371. The corresponding 27-nucleotide deletion was found in alpha-spectrin mRNA. However, exon 8 of spectrin alpha-gene failed to disclose this deletion. Instead, an A to G substitution appeared in position 3 of codon 362, leading to the occurrence of the critical GU dinucleotide within a cryptic 5'-splice site surrounding codon 362. This event would account for the splicing out of codons 363 to 371. The reading frame was preserved and even amino acid 362 (AGG, Arg) remained unaltered. As in most spectrin alpha-chain elliptocytogenic variants, the change involved a helix 3. This is the first elliptocytogenic mutation recorded in repeat alpha 4. ( info)

16/74. spectrin Jendouba: an alpha II/31 spectrin variant that is associated with elliptocytosis and carries a mutation distant from the dimer self-association site.

    spectrin Jendouba (alpha II/31) was found in a Tunisian family. In the heterozygous state, it is associated with asymptomatic elliptocytosis and a minimal defect in spectrin dimer self-association. On partial digestion of spectrin with trypsin, an abnormal cleavage appeared following Lys 788. Peptide and dna sequencing indicated that the responsible mutation is alpha 791 Asp   Glu (GAC   GAA). As in most alpha-spectrin variants associated with elliptocytosis, the change alters helix 3 of the proposed triple helical model of spectrin structure. Modified helix 3 in repeat alpha 8 is the most distant from the N-terminus of alpha-spectrin in known variants associated with elliptocytosis. ( info)

17/74. Molecular demonstration of SLC4A1 gene deletion in two Mexican patients with Southeast Asian ovalocytosis.

    We describe the finding of two Mexican patients with a specific 27-bp deletion in the solute carrier family 4 gene (SLC4A1delta27) (also known as the band 3 gene found on chromosome 17q21-q22), characteristic of Southeast Asian ovalocytosis (SAO). The patients were asymptomatic, and the initial diagnosis was made by microscopic observation of the presence of typical stomatocytic ovalocytes. The gene deletion was confirmed by PCR and dna sequencing. Both patients were heterozygous for the deletion. One patient is from Tabasco state, in southeastern mexico, a malaria-endemic zone. The other patient is from mexico City, which is not a malaria-endemic area. Their families have no non-Mexican ancestors and their previous generations were born in mexico. Both patients carry the HLA-B*3501 subtype, characteristic of Amerindians and Asian populations. Familial and HLA data led us to conclude that these two patients are the first report of SLC4A1delta27 in Amerindians. The nucleotide analysis showing a perfect match sequence between Southeast Asian and Mexican patients suggests, but does not prove, that the Mexican gene is not a de novo mutation. Instead, this gene might be the result of migration of individuals with Asian ancestry into the Mexican gene pool. We are looking for other families with the mutation to detect, by HLA analysis, the ancient ethnic origin of these patients. ( info)

18/74. Molecular analysis of hereditary elliptocytosis with reduced protein 4.1 in the French Northern Alps.

    4.1(-) hereditary elliptocytosis (HE) is a variety of elliptocytosis resulting from the reduction (heterozygosity) or the absence (homozygosity) of protein 4.1. It is nearly always encountered in its heterozygous form. It has been found among Caucasians and North Africans in a sporadic fashion. We report the study on nine family cases of 4.1(-) HE. They were recruited independently (to the exclusion of any other variety of HE) in a limited area around the city of Annecy (French Northern Alps). The mode of genetic transmission, as well as the clinical, morphologic, and protein phenotypes fully conformed to the classical description. Western blots ruled out the existence of any protein 4.1 species of abnormal size. No obvious dna rearrangement was detectable in any of the nine families with three 4.1 cDNA probes covering the entire coding sequence and part of the flanking 5' and 3' untranslated sequences. On the basis of five polymorphic sites (Bgl II, 2; Pvu II, 3), we found five different haplotypes in normal members of the 4.1(-) families. 4.1(-) HE was associated with the most common haplotype in all the propositi. 4.1 mRNA was studied in four families. Dot-blot hybridization experiments and Northern blots failed to show any detectable change in three families. On the other hand, they showed a 2-kb deletion in the 4.1(-) messenger rna 5'-moiety in one family. These findings emphasize the heterogeneity of 4.1(-) HE at the molecular level. ( info)

19/74. Occurrence of the alpha I 22 Arg

   His (CGT   CAT) spectrin mutation in tunisia: potential association with severe elliptopoikilocytosis.     A category of spectrin alpha I domain variants are manifested by the increase of the alpha I 74 kDa fragment at the expense of the parent 80 kDa fragment following partial tryptic digestion. We describe a particular case of alpha I/74 abnormality in a Tunisian family. The propositus was severely ill and had an elliptopoikilocytosis. To the contrary, his father, who carried the same alpha I/74 variant, displayed no clinical signs and a few elliptocytes. The increase of the alpha I 74 kDa fragment was more pronounced in the propositus than in his father. Unexpectedly, the spectrin content was reduced to similar (and limited) extents in both of them, and the father displayed nearly as pronounced an increase of the spectrin dimer percentage as the propositus following low ionic strength extraction. in vitro spectrin dimer reconstitution experiments indicated that the primary mutation was located in the alpha-chain itself (not in the beta-chain as is the case in some alpha I/74 mutants). Following polymerase chain reaction (PCR) amplification, cloning and sequencing of exon 2 of spectrin alpha-gene in the father, we found the G   A substitution at position 2 of codon 22 (CGT   CAT; Arg   His). This mutation has been recently discovered in a family of French descent. Dot blot hybridization confirmed that the substitution was transmitted with the alpha I/74 abnormality. As previously shown, the enhancement of its expression level in the propositus, with respect to the father, was accounted for by the presence of a factor carried by the alpha-spectrin allele in trans and transmitted by the mother. ( info)

20/74. An insertional frameshift mutation of the beta-spectrin gene associated with elliptocytosis in spectrin nice (beta 220/216).

    spectrin Nice (beta 220/216) is a spectrin variant associated with a shortened beta chain found in a patient with elliptocytosis. The shortened beta chain (beta' chain) appeared as an additional band of approximately 216 Kd on sodium dodecyl sulfate-polyacrylamide gel electrophoresis and was defective in its ability to be phosphorylated. There were increased amounts of spectrin dimers in crude spectrin extracts from the propositus and the association constant of spectrin dimer self-association was decreased. There was an associated increase of the alpha I 74-Kd fragment from the alpha chain after partial trypic digestion of spectrin. To identify the underlying molecular defect, we analyzed cDNA for beta spectrin obtained by polymerase chain reaction amplification of reverse-transcribed reticulocyte messenger rna from peripheral blood of the propositus. dna sequencing of individual as well as pooled subclones showed that two extra bases (GA) are inserted in codon no. 2046 in one allele of the beta-spectrin gene. The insertion results in a frameshift mutation and generates an aberrant C-terminus truncated by about 4 Kd, consistent with the estimated size of the beta' chain observed. By allele-specific oligonucleotide hybridization, the insertion was shown to be present in the propositus and absent in his parents, confirming a previous proposal that it is a de novo mutation. The determination of the location of the mutation in spectrin Nice points to specific regions of the beta-spectrin chain where phosphorylation may occur. A model is proposed to describe the interaction between the alpha- and beta-spectrin chains and to explain the effects of the mutation found in spectrin Nice on the trypsin digestion pattern of its associated alpha chain. ( info)
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