The occurrence of point mutation alpha-thalassaemia and of complex combinations of haemoglobin defects is underestimated. Haemoglobinopathies, the most frequent monogenic recessive autosomal disorder in man, occur predominantly in Mediterranean, African and Asiatic populations. However, countries of immigration with a low incidence in the indigenous population, are now confronted with a highly heterogeneous array of imported defects. Furthermore, the occurrence of severe phenotypes is bound to increase in the near future because of the endogamous growth of the ethnical minorities and the lack of prevention. We describe an Afghan family in which both partners of a consanguineous relationship are carriers of a beta- as well as an alpha-thalassaemia determinant. The combination of defects was revealed by the in vitro measurement of the beta/alpha biosynthetic ratio and was characterised at the DNA level. The molecular defects involved are the Cd5(-CT), a Mediterranean beta zero-thalassaemia mutation, and the alpha 2(zero/+)-thalassaemia AATA(-AA) polyadenylation defect. The alpha-thalassemia defect is a rare RNA-processing mutant described only twice before in heterozygous form in Asian-Indian patients. The mutation suppresses the expression of a alpha 2 gene and reduces the expression of the less efficient, 3' located alpha 1 gene as well, inducing a near alpha zero-thalassaemia phenotype. This defect is now described for the first time in the homozygous condition in one of the children who, in addition to being homozygous for the alpha-thalassaemia point mutation, is also a carrier of the beta zero-thalassaemia defect. A previously described homozygous case of the alpha (zero/+)-thalassaemia condition, caused by a similar polyadenylation defect, was characterised by a severe HbH disease. However, the patient described here present at 7 years of age with severe caries, like his beta-thalassaemia homozygous brother but without hepatosplenomegaly, haemolysis or severe anaemia. The haematological analysis revealed 9.5 g/dl Hb; 5.4 x 10(12)/I RBC; 0.33 I/I PCV; 61 fl MCV; 17.6 pg MCH and 6.2% of HbA2. The biosynthetic ratio beta:alpha was 1.6 and no HbH fraction was detectable either on electrophoresis or as inclusion bodies. The parents reported no complications during pregnancy, at birth, or in the neonatal period in rural Afghanistan. We presume therefore that the counterbalancing effect induced by the co-existing beta-thalassaemia defect could have modified a potentially severe perinatal HbH disease into a strongly hypochromic but well compensated 'alpha zero-like heterozygous' thalassaemia phenotype. The risk of a severe HbH disease, could have been easily missed in this family which was referred because of a child affected with beta-thalassaemia major.

Female↗

PubMedDate not supplied

mtDNA provides the first known marker distinguishing proto-Indians from the other Caucasoids; it probably predates the diversification between Indians and Orientals.

The concomitant presence of the two sites Ddel at 10,394 and Alul at 10,397 has been considered an East-Asian marker of ancient origin (it was also observed in Australians, Melanesians and Native Americans). Unexpectedly, it was found in more than 50% of Indians (133 Hindus and 30 Tribals) who had shown Caucasoid characteristics not only at nuclear DNA but also at mtDNA level. It can therefore no longer be considered an exclusively East-Asian mtDNA feature. The analysis of more than 200 Caucasoids, mainly from the Mediterranean basin, showed that it is only sporadically present in these people. Thus it represents the first known marker which distinguishes Indians from the other Caucasoids. The lack of this marker in Indian mtDNA molecules carrying Caucasoid characteristics suggests that it predates the invasion of India by speakers of an Indo-European language and, if it is valid to extrapolate from Near Eastern data, the arrival in India of the farmers who spread the Dravidian language. If this polymorphism had a common origin in both Orientals and Indians, it should also predate the diversification between ancient Indians and Mongoloids.

Africa South of the Sahara↗

PubMedDate not supplied

Hemoglobin Sabine [beta 91 (F7) Leu-->Pro]: occurrence in a Sardinian individual with hemolytic anemia and inclusion bodies.

BACKGROUND: Hemoglobin (Hb) Sabine (beta 91 Leu-->Pro) is an unstable variant detected for the first time in a 16-year-old Scottish-English-German girl affected by moderately severe hemolytic anemia. A second case was described in a patient of Yugoslavian descent. We report another case of this Hb variant arising as a de novo mutation in a Sardinian patient. METHODS: Definition of the mutation was obtained by DNA direct sequencing on amplified beta-globin gene, as well as by structural analysis of the hemoglobin variant. RESULTS AND CONCLUSION: The patient presented a moderately severe hemolytic anemia with red blood cell inclusion bodies. Hemoglobin electrophoresis showed that quantitatively the abnormal fraction represented 9% of the total Hb amount. beta globin gene analysis revealed a single nucleotide substitution, T-->C, at codon 91, which gives rise to a leucine-->proline substitution. Structural analysis of the variant confirmed the amino acid substitution (Leu-->Pro) predicted by DNA sequencing.

Adult↗

PubMedDate not supplied

Detection of K-ras mutations by denaturing gradient gel electrophoresis (DGGE): a study on pancreatic cancer.

In pancreatic neoplasias mutations in the first exon (codon 12) of K-ras gene occur at high frequency and seem to have a diagnostic significance. We set up the DGGE conditions to search for these mutations in pancreatic tumor sample DNAs. All samples were directly classified by simply comparing their DGGE patterns with those of control cell lines carrying known K-ras base substitutions. We found a mutation frequency of 73% in pancreatic adenocarcinoma, whereas no mutations were observed in benign lesions. The non-isotopic method we used turned out to be rapid and sensitive. DGGE could therefore be utilized for the detection of K-ras mutations in pancreatic lesions, to evaluate their actual or potential malignancy. In general, DGGE could be useful for K-ras gene screening on pathological tissue samples.

Adenocarcinoma↗