PubMed Health⌕ Search

Biomedical subjects

H Kazazian

Publications and source records attributed to H Kazazian.

9 recordsLinked to original sources
PubMed1999

Short-term correction of factor VIII deficiency in a murine model of hemophilia A after delivery of adenovirus murine factor VIII in utero.

Development of in utero gene transfer approaches may provide therapies for genetic disorders with perinatal morbidity. In hemophilia A, prenatal and postnatal bleeding may be catastrophic, and modest increments in factor VIII (FVIII) activity are therapeutic. We performed transuterine i.p. gene transfer at day 15 of gestation in a murine model of hemophilia A. Normal, carrier (X(H)X), and FVIII-deficient (X(H)Y and X(H)X(H)) fetuses injected with adenoviral vectors carrying luciferase or beta-galactosidase reporter genes showed high-level gene expression with 91% fetal survival. The live-born rates of normal and FVIII-deficient animals injected in utero with adenovirus murine FVIII (3.3 x 10(5) plaque-forming units) was 87%. FVIII activity in plasma was 50.7 +/- 10.5% of normal levels at day 2 of life, 7.2 +/- 2.2% by day 15 of life, and no longer detectable at day 21 of life in hemophilic animals. Injection of higher doses of murine FVIII adenovirus at embryonic day 15 produced supranormal levels of FVIII activity in the neonatal period. PCR analysis identified viral genomes primarily in the liver, intestine, and spleen, although adenoviral DNA was detected in distal tissues when higher doses of adenovirus were administered. These studies show that transuterine i.p. injection of adenoviral vectors produces therapeutic levels of circulating FVIII throughout the neonatal period. The future development of efficient and persisting vectors that produce long-term gene expression may allow for in utero correction of genetic diseases originating in the fetal liver, hematopoietic stem cells, as well as other tissues.

Adenoviridae↗
PubMed1996

A combined analysis of D22S278 marker alleles in affected sib-pairs: support for a susceptibility locus for schizophrenia at chromosome 22q12. Schizophrenia Collaborative Linkage Group (Chromosome 22).

Several groups have reported weak evidence for linkage between schizophrenia and genetic markers located on chromosome 22q using the lod score method of analysis. However these findings involved different genetic markers and methods of analysis, and so were not directly comparable. To resolve this issue we have performed a combined analysis of genotypic data from the marker D22S278 in multiply affected schizophrenic families derived from 11 independent research groups worldwide. This marker was chosen because it showed maximum evidence for linkage in three independent datasets (Vallada et al., Am J Med Genet 60:139-146, 1995; Polymeropoulos et al., Neuropsychiatr Genet 54:93-99, 1994; Lasseter et al., Am J Med Genet, 60:172-173, 1995. Using the affected sib-pair method as implemented by the program ESPA, the combined dataset showed 252 alleles shared compared with 188 alleles not share (chi-square 9.31, 1df, P = 0.001) where parental genotype data was completely known. When sib-pairs for whom parental data was assigned according to probability were included the number of alleles shared was 514.1 compared with 437.8 not shared (chi-square 6.12, 1df, P = 0.006). Similar results were obtained when a likelihood ratio method for sib-pair analysis was used. These results indicate that may be a susceptibility locus for schizophrenia at 22q12.

Alleles↗
PubMed1993

Neurobehavioral effects of the fragile X premutation in adult women: a controlled study.

Although previous studies have suggested that the fragile X premutation (fra [X] pM) does not cause deleterious effects, methodological constraints have prevented more definitive conclusions from being reached. In this report, we describe the neuropsychiatric and cognitive-neuropsychological status of 34 adult women with the fra (X) pM, as compared with a well-matched control group of 41 mothers of fra (X)-negative children with developmental disability. The results indicate that there are no meaningful differences between adult women with the fra (X) pM and control subjects with respect to cognitive abilities or profile, neuropsychological function, psychiatric diagnoses or symptoms, and self-rated personality profile. No measure for either group showed evidence of functioning outside the normal range except for a high lifetime prevalence of major depression in both groups. Additional exploratory analyses within the fra (X) group showed no significant effect of either the size of the fra (X) insert or X chromosome inactivation pattern in leukocytes, on any measure of neurobehavioral function. These findings provide additional information to professionals providing genetic counseling to, and assessment of, fra (X) families.

Adult↗
PubMed1987

Linkage analysis of neurofibromatosis.

Linkage analysis of neurofibromatosis was performed using genes on chromosomes 1, 8, 11, and 12. No linkage was found between NF and C-myc, AT 3, IGF-1, PTH, and gamma globin genes. Evidence for linkage was found between C-ets 1, on the long arm of chromosome 11 and NF in two families with a lod score of 1.88 at theta = 0. More families are being studied to confirm this linkage.

Chromosomes, Human, Pair 11↗
PubMed1986

Chinese A gamma fetal hemoglobin: C to T substitution at position-196 of the A gamma gene promoter.

The molecular basis for the hereditary persistence of fetal hemoglobin (HPFH) phenotype was studied in a Chinese individual who was heterozygous for a nondeletion form of A gamma-HPFH. Both allelic A gamma-globin genes were isolated by molecular cloning and subjected to nucleotide sequence analysis. One A gamma gene promoter showed a cytosine to thymine transition at position -196, whereas the other promoter was normal. This mutation at position -196 has now ben found in unrelated individuals with the A gamma-HPFH phenotype from Italy, Sardinia, and China, suggesting that it may have arisen independently. The implications of this mutation for models of fetal globin gene switching are discussed.

Adult↗
PubMed1979

Oxygen transport in a woman with hemoglobin Hope/beta+ thalassemia.

Because their blood may "unload" oxygen more readily than normal, people with hemoglobin of low oxygen affinity might be expected to be anemic. We have studied a woman with hemoglobin Hope/beta+ thalassemia, whose hemoglobin level was 10.4 to 12.3 gm/dl (normal 14 +/- 2) despite a P50 of 41 mm Hg (normal 26). Her cardiac index was normal, yielding a calculated mixed venous PO2 of 51 mm Hg (normal 34 to 49). Oxygen transport in patients with low oxygen affinity can be maintained by a variety of homeostatic responses, only one of which is altered erythropoiesis.

Adult↗
PubMed1977

Postsynthetic deamidation of hemoglobin Providence (beta 82 Lys replaced by Asn, Asp) and its effect on oxygen transport.

Carriers of hemoglobin Providence have three types of beta chain in their hemolysates. The two abnormal chains have asparagine (Providence N, Prov N) or aspartic acid (Providence D) at position beta 82, instead of lysine. In vitro, only two beta chains are synthesized by reticulocytes of carriers, betaA and betaProv N. In vivo studies showed that the specific activity of Providence N was initially 10-fold higher than that of Providence D; the specific activities of the two labeled hemoglobins were approximately equal 5 wk after injection of isotope. Oxygen affinity of carriers' blood was somewhat increased, but they were not polycythemic. The affinity of the purified hemoglobins Providence was decreased. Addition of 2, 3 diphosphoglycerate had little effect on the affinity of either hemoglobin component, and addition of inositol hexaphosphate produced no change in the affinity of Providence D. These studies demonstrate that Providence N is deamidated to Providence D during the life span of the erythrocyte, and suggest this finding may represent only an easily observed prototype of posttranslational modification of proteins in general. Despite and abnormal P50 of the blood, oxygen transport is probably normal in carriers of the abnormal hemoglobins.

Adolescent↗