The Experts below are selected from a list of 114 Experts worldwide ranked by ideXlab platform

Narla Mohandas - One of the best experts on this subject based on the ideXlab platform.

  • An update on the pathogenesis and diagnosis of Diamond–Blackfan Anemia
    F1000Research, 2018
    Co-Authors: Lydie Da Costa, Anupama Narla, Narla Mohandas
    Abstract:

    Diamond–Blackfan Anemia (DBA) is a rare Congenital Hypoplastic Anemia characterized by a block in erythropoiesis at the progenitor stage, although the exact stage at which this occurs remains to be fully defined. DBA presents primarily during infancy with macrocytic Anemia and reticulocytopenia with 50% of cases associated with a variety of Congenital malformations. DBA is most frequently due to a sporadic mutation (55%) in genes encoding several different ribosomal proteins, although there are many cases where there is a family history of the disease with varying phenotypes. The erythroid tropism of the disease is still a matter of debate for a disease related to a defect in global ribosome biogenesis. Assessment of biological features in conjunction with genetic testing has increased the accuracy of the diagnosis of DBA. However, in certain cases, it continues to be difficult to firmly establish a diagnosis. This review will focus on the diagnosis of DBA along with a description of new advances in our understanding of the pathophysiology and treatment recommendations for DBA.

  • Nucleolar localization of RPS19 protein in normal cells and mislocalization due to mutations in the nucleolar localization signals in 2 Diamond-Blackfan Anemia patients: potential insights into pathophysiology
    Blood, 2003
    Co-Authors: Lydie Da Costa, Jason Fixler, Gil Tchernia, Charlotte M. Niemeyer, Philippe Gascard, Annie Lo, Joerg J Meerpohl, Joel-anne Chasis, Narla Mohandas
    Abstract:

    Ribosomal protein S19 (RPS19) is frequently mutated in Diamond-Blackfan Anemia (DBA), a rare Congenital Hypoplastic Anemia. Recent studies have shown that RPS19 expression decreases during terminal erythroid differentiation. Currently no information is available on the subcellular localization of normal RPS19 and the potential effects of various RPS19 mutations on cellular localization. In the present study, using wild-type and mutant RPS19 cDNA, we explored the subcellular distribution of normal and mutant proteins in a fibroblast cell line (Cos-7 cells). RPS19 was detected primarily in the nucleus, and more specifically in the nucleoli, where RPS19 colocalized with the nucleolar protein nucleolin. Using various N-terminal and C-terminal deletion constructs, we identified 2 nucleolar localization signals (NoSs) in RPS19: the first comprising amino acids Met1 to Arg16 in the NH 2 -terminus and the second comprising Gly120 to Asn142 in the COOH-terminus. Importantly, 2 mutations identified in DBA patients, Val15Phe and Gly127Gln, each of which localized to 1 of the 2 NoS, failed to localize RPS19 to the nucleolus. In addition to their mislocalization, there was a dramatic decrease in the expression of the 2 mutant proteins compared to the wild type. This decrease in protein expression was specific for the mutant RPS19, since expression of other proteins was normal. The present findings enable us to document the nucleolar localization signals in RPS19 and help define the phenotypic consequences of some mutations in RPS19 in DBA.

  • Evidence for linkage of familial Diamond-Blackfan Anemia to chromosome 8p23.3-p22 and for non-19q non-8p disease
    Blood, 2001
    Co-Authors: Hanna T. Gazda, Jeffrey M. Lipton, Thiébaut-noël Willig, Narla Mohandas, Gil Tchernia, Sarah E. Ball, Charlotte M. Niemeyer, Mark J. Daly, Anna Ploszynska, Karen A. Orfali
    Abstract:

    Diamond-Blackfan Anemia (DBA) is a rare Congenital Hypoplastic Anemia that usually presents early in infancy and is inherited in 10% to 20% of cases. Linkage analysis has shown that DBA in many of both dominant and recessive DBA families mapped to chromosome 19q13.2 leading to the cloning of a gene on chromosome 19q13.2 that encodes a ribosomal protein, RPS19. However, subsequently, mutations of the RPS19 gene have only been identified in 25% of all patients with DBA. This study analyzed 14 multiplex DBA families, 9 of which had 19q13.2 haplotypes inconsistent with 19q linkage. A genome-wide search for linked loci suggested the presence of a second DBA locus in a 26.4-centimorgan (cM) interval on human chromosome 8p. Subsequently, 24 additional DBA families were ascertained and all 38 families were analyzed with additional polymorphic markers on chromosome 8p. In total, 18 of 38 families were consistent with linkage to chromosome 8p with a maximal LOD score with heterogeneity of 3.55 at D8S277 assuming 90% penetrance. The results indicate the existence of a second DBA gene in the 26.4-cM telomeric region of human chromosome 8p23.3-p22, most likely within an 8.1-cM interval flanked by D8S518 and D8S1825. Seven families were inconsistent with linkage to 8p or 19q and did not reveal mutations in the RPS19 gene, suggesting further genetic heterogeneity. (Blood. 2001;97:2145-2150)

  • Diamond-Blackfan Anemia.
    Current Opinion in Pediatrics, 2001
    Co-Authors: Lydie Da Costa, Thiébaut-noël Willig, Jason Fixler, Narla Mohandas, Gil Tchernia
    Abstract:

    : Diamond-Blackfan Anemia (DBA) is a rare, Congenital Hypoplastic Anemia often diagnosed early in infancy. A moderate to severe aregenerative Anemia is found in association with erythroblastopenia in an otherwise normocellular bone marrow. In 40% of these infants with DBA, diverse developmental abnormalities are also noted. A majority of patients with DBA respond to steroid therapy. Recent molecular studies have identified mutations in the gene encoding the ribosomal protein RPS19 on chromosome 19 in 25% of patients with DBA. In another subset of patients, linkage analysis has identified another locus on chromosome 8p in association with DBA. There are, however, other cases of DBA that are linked neither to the RPS19 gene nor to the locus on 8p, implying the involvement of yet-to-be-defined genetic defects in the cause of DBA. The pathogenesis of DBA is still to be fully defined and it is anticipated that further molecular studies will lead to a better understanding of this complex disease.

Bertil Glader - One of the best experts on this subject based on the ideXlab platform.

  • Congenital Hypoplastic Anemia (Diamond — Blackfan Anemia)
    Aplastic Anemia and Other Bone Marrow Failure Syndromes, 1990
    Co-Authors: Bertil Glader
    Abstract:

    Pure red blood cell (RBC) aplasia in children is a relatively common problem that usually represents a “pure erythroid abnormality” without other associated medical problems. This is in sharp contrast to the much rarer occurrences of RBC aplasia in adults, which often are associated with autoimmune disease, drugs, toxic exposures, malignancies, and, in a large fraction of patients, thymomas. The three major causes of pure red cell aplasia in children are Diamond — Blackfan Anemia (DBA) transient erythroblastopenia of childhood (TEC), and acquired RBC hypoplasia associated with chronic hemolytic Anemia. The major focus of this report is to summarize some of the current clinical problems related to Diamond — Blackfan Anemia.

  • Congenital Hypoplastic diamond blackfan Anemia in seven members of one kindred
    American Journal of Medical Genetics, 1990
    Co-Authors: David H Viskochil, Bertil Glader, John C Carey, Gerald Rothstein, D Robert M D Christensen
    Abstract:

    : Congenital Hypoplastic (Diamond-Blackfan) Anemia is a rare macrocytic Anemia, generally presenting during infancy or childhood. The condition usually occurs sporadically or in a pattern consistent with autosomal recessive inheritance, although autosomal dominant transmission has been proposed in some kindreds. We report the largest known kindred of Congenital Hypoplastic Anemia, with at least 7 affected individuals over 3 generations, and propose that studies of this kindred may be useful for identifying the mechanism by which their genetic abnormality results in Congenital Hypoplastic Anemia. Erythropoietic investigations on relatives show no inhibitors of erythropoiesis in serum, T-lymphocytes, or macrophages. Their erythroid progenitor cells (CFU-E and BFU-E) were generally quantitatively normal, and were capable of rapid proliferation, as judged by cell-cycle shortening. However, their erythroid progenitors displayed a relative insensitivity to recombinant erythropoietin, and produced relatively few normoblasts per erythroid progenitor cell. We propose that these and subsequent studies may be helpful in selecting candidate genes responsible for the molecular defect in this kindred.

  • Congenital Hypoplastic Anemia diamond blackfan Anemia
    1990
    Co-Authors: Bertil Glader
    Abstract:

    Pure red blood cell (RBC) aplasia in children is a relatively common problem that usually represents a “pure erythroid abnormality” without other associated medical problems. This is in sharp contrast to the much rarer occurrences of RBC aplasia in adults, which often are associated with autoimmune disease, drugs, toxic exposures, malignancies, and, in a large fraction of patients, thymomas. The three major causes of pure red cell aplasia in children are Diamond — Blackfan Anemia (DBA) transient erythroblastopenia of childhood (TEC), and acquired RBC hypoplasia associated with chronic hemolytic Anemia. The major focus of this report is to summarize some of the current clinical problems related to Diamond — Blackfan Anemia.

A Van Haeringen - One of the best experts on this subject based on the ideXlab platform.

  • Congenital Hypoplastic Anemia another example of autosomal dominant transmission
    American Journal of Medical Genetics, 1994
    Co-Authors: V Gojic, E Vant T Veerkorthof, L J Bosch, W H Puyn, A Van Haeringen
    Abstract:

    Congenital Hypoplastic Anemia (CHA) or Blackfan-Diamond Anemia (BDA) is a rare Congenital abnormality of erythropoiesis characterized by normochromic, macrocytic Anemia presenting in infancy or early childhood. Associated phenotypic abnormalities such as triphalangeal thumbs and cleft lip and/or palate are found in 70% of cases. Although most cases are sporadic, several reports suggest either autosomal dominant or autosomal recessive inheritance. We report on a 3 generation family with autosomal dominant inheritance of CHA. © 1994 Wiley-Liss, Inc.

Lydie Da Costa - One of the best experts on this subject based on the ideXlab platform.

  • An update on the pathogenesis and diagnosis of Diamond–Blackfan Anemia
    F1000Research, 2018
    Co-Authors: Lydie Da Costa, Anupama Narla, Narla Mohandas
    Abstract:

    Diamond–Blackfan Anemia (DBA) is a rare Congenital Hypoplastic Anemia characterized by a block in erythropoiesis at the progenitor stage, although the exact stage at which this occurs remains to be fully defined. DBA presents primarily during infancy with macrocytic Anemia and reticulocytopenia with 50% of cases associated with a variety of Congenital malformations. DBA is most frequently due to a sporadic mutation (55%) in genes encoding several different ribosomal proteins, although there are many cases where there is a family history of the disease with varying phenotypes. The erythroid tropism of the disease is still a matter of debate for a disease related to a defect in global ribosome biogenesis. Assessment of biological features in conjunction with genetic testing has increased the accuracy of the diagnosis of DBA. However, in certain cases, it continues to be difficult to firmly establish a diagnosis. This review will focus on the diagnosis of DBA along with a description of new advances in our understanding of the pathophysiology and treatment recommendations for DBA.

  • Nucleolar localization of RPS19 protein in normal cells and mislocalization due to mutations in the nucleolar localization signals in 2 Diamond-Blackfan Anemia patients: potential insights into pathophysiology
    Blood, 2003
    Co-Authors: Lydie Da Costa, Jason Fixler, Gil Tchernia, Charlotte M. Niemeyer, Philippe Gascard, Annie Lo, Joerg J Meerpohl, Joel-anne Chasis, Narla Mohandas
    Abstract:

    Ribosomal protein S19 (RPS19) is frequently mutated in Diamond-Blackfan Anemia (DBA), a rare Congenital Hypoplastic Anemia. Recent studies have shown that RPS19 expression decreases during terminal erythroid differentiation. Currently no information is available on the subcellular localization of normal RPS19 and the potential effects of various RPS19 mutations on cellular localization. In the present study, using wild-type and mutant RPS19 cDNA, we explored the subcellular distribution of normal and mutant proteins in a fibroblast cell line (Cos-7 cells). RPS19 was detected primarily in the nucleus, and more specifically in the nucleoli, where RPS19 colocalized with the nucleolar protein nucleolin. Using various N-terminal and C-terminal deletion constructs, we identified 2 nucleolar localization signals (NoSs) in RPS19: the first comprising amino acids Met1 to Arg16 in the NH 2 -terminus and the second comprising Gly120 to Asn142 in the COOH-terminus. Importantly, 2 mutations identified in DBA patients, Val15Phe and Gly127Gln, each of which localized to 1 of the 2 NoS, failed to localize RPS19 to the nucleolus. In addition to their mislocalization, there was a dramatic decrease in the expression of the 2 mutant proteins compared to the wild type. This decrease in protein expression was specific for the mutant RPS19, since expression of other proteins was normal. The present findings enable us to document the nucleolar localization signals in RPS19 and help define the phenotypic consequences of some mutations in RPS19 in DBA.

  • Diamond-Blackfan Anemia.
    Current Opinion in Pediatrics, 2001
    Co-Authors: Lydie Da Costa, Thiébaut-noël Willig, Jason Fixler, Narla Mohandas, Gil Tchernia
    Abstract:

    : Diamond-Blackfan Anemia (DBA) is a rare, Congenital Hypoplastic Anemia often diagnosed early in infancy. A moderate to severe aregenerative Anemia is found in association with erythroblastopenia in an otherwise normocellular bone marrow. In 40% of these infants with DBA, diverse developmental abnormalities are also noted. A majority of patients with DBA respond to steroid therapy. Recent molecular studies have identified mutations in the gene encoding the ribosomal protein RPS19 on chromosome 19 in 25% of patients with DBA. In another subset of patients, linkage analysis has identified another locus on chromosome 8p in association with DBA. There are, however, other cases of DBA that are linked neither to the RPS19 gene nor to the locus on 8p, implying the involvement of yet-to-be-defined genetic defects in the cause of DBA. The pathogenesis of DBA is still to be fully defined and it is anticipated that further molecular studies will lead to a better understanding of this complex disease.

Gil Tchernia - One of the best experts on this subject based on the ideXlab platform.

  • Nonsense-mediated and nonstop decay of ribosomal protein S19 mRNA in Diamond-Blackfan Anemia.
    Human Mutation, 2004
    Co-Authors: Andrew Chatr-aryamontri, Irma Dianzani, Gil Tchernia, Mara Angelini, Emanuela Garelli, Ugo Ramenghi, Fabrizio Loreni
    Abstract:

    Mutations in the ribosomal protein (RP)S19 gene have been found in about 25% of the cases of Diamond-Blackfan Anemia (DBA), a rare Congenital Hypoplastic Anemia that includes variable physical malformations. Various mutations have been identified in the RPS19 gene, but no investigations regarding the effect of these alterations on RPS19 mRNA levels have been performed. It is well established that mutated mRNA containing a premature stop codon (PTC) or lacking a stop codon can be rapidly degraded by specific mechanisms called nonsense mediated decay (NMD) and nonstop decay. To study the involvement of such mechanisms in DBA, we analyzed immortalized lymphoblastoid cells and primary fibroblasts from patients presenting different kinds of mutations in the RPS19 gene, generating allelic deletion, missense, nonsense, and nonstop messengers. We found that RPS19 mRNA levels are decreased in the cells with allelic deletion and, to a variable extent, also in all the cell lines with PTC or nonstop mutations. Further analysis showed that translation inhibition causes a stabilization of the mutated RPS19 mRNA. Our findings indicate that NMD and nonstop decay affect the expression of mutated RPS19 genes; this may help to clarify genotype-phenotype correlations in DBA. © 2004 Wiley-Liss, Inc.

  • Nucleolar localization of RPS19 protein in normal cells and mislocalization due to mutations in the nucleolar localization signals in 2 Diamond-Blackfan Anemia patients: potential insights into pathophysiology
    Blood, 2003
    Co-Authors: Lydie Da Costa, Jason Fixler, Gil Tchernia, Charlotte M. Niemeyer, Philippe Gascard, Annie Lo, Joerg J Meerpohl, Joel-anne Chasis, Narla Mohandas
    Abstract:

    Ribosomal protein S19 (RPS19) is frequently mutated in Diamond-Blackfan Anemia (DBA), a rare Congenital Hypoplastic Anemia. Recent studies have shown that RPS19 expression decreases during terminal erythroid differentiation. Currently no information is available on the subcellular localization of normal RPS19 and the potential effects of various RPS19 mutations on cellular localization. In the present study, using wild-type and mutant RPS19 cDNA, we explored the subcellular distribution of normal and mutant proteins in a fibroblast cell line (Cos-7 cells). RPS19 was detected primarily in the nucleus, and more specifically in the nucleoli, where RPS19 colocalized with the nucleolar protein nucleolin. Using various N-terminal and C-terminal deletion constructs, we identified 2 nucleolar localization signals (NoSs) in RPS19: the first comprising amino acids Met1 to Arg16 in the NH 2 -terminus and the second comprising Gly120 to Asn142 in the COOH-terminus. Importantly, 2 mutations identified in DBA patients, Val15Phe and Gly127Gln, each of which localized to 1 of the 2 NoS, failed to localize RPS19 to the nucleolus. In addition to their mislocalization, there was a dramatic decrease in the expression of the 2 mutant proteins compared to the wild type. This decrease in protein expression was specific for the mutant RPS19, since expression of other proteins was normal. The present findings enable us to document the nucleolar localization signals in RPS19 and help define the phenotypic consequences of some mutations in RPS19 in DBA.

  • Evidence for linkage of familial Diamond-Blackfan Anemia to chromosome 8p23.3-p22 and for non-19q non-8p disease
    Blood, 2001
    Co-Authors: Hanna T. Gazda, Jeffrey M. Lipton, Thiébaut-noël Willig, Narla Mohandas, Gil Tchernia, Sarah E. Ball, Charlotte M. Niemeyer, Mark J. Daly, Anna Ploszynska, Karen A. Orfali
    Abstract:

    Diamond-Blackfan Anemia (DBA) is a rare Congenital Hypoplastic Anemia that usually presents early in infancy and is inherited in 10% to 20% of cases. Linkage analysis has shown that DBA in many of both dominant and recessive DBA families mapped to chromosome 19q13.2 leading to the cloning of a gene on chromosome 19q13.2 that encodes a ribosomal protein, RPS19. However, subsequently, mutations of the RPS19 gene have only been identified in 25% of all patients with DBA. This study analyzed 14 multiplex DBA families, 9 of which had 19q13.2 haplotypes inconsistent with 19q linkage. A genome-wide search for linked loci suggested the presence of a second DBA locus in a 26.4-centimorgan (cM) interval on human chromosome 8p. Subsequently, 24 additional DBA families were ascertained and all 38 families were analyzed with additional polymorphic markers on chromosome 8p. In total, 18 of 38 families were consistent with linkage to chromosome 8p with a maximal LOD score with heterogeneity of 3.55 at D8S277 assuming 90% penetrance. The results indicate the existence of a second DBA gene in the 26.4-cM telomeric region of human chromosome 8p23.3-p22, most likely within an 8.1-cM interval flanked by D8S518 and D8S1825. Seven families were inconsistent with linkage to 8p or 19q and did not reveal mutations in the RPS19 gene, suggesting further genetic heterogeneity. (Blood. 2001;97:2145-2150)

  • Diamond-Blackfan Anemia.
    Current Opinion in Pediatrics, 2001
    Co-Authors: Lydie Da Costa, Thiébaut-noël Willig, Jason Fixler, Narla Mohandas, Gil Tchernia
    Abstract:

    : Diamond-Blackfan Anemia (DBA) is a rare, Congenital Hypoplastic Anemia often diagnosed early in infancy. A moderate to severe aregenerative Anemia is found in association with erythroblastopenia in an otherwise normocellular bone marrow. In 40% of these infants with DBA, diverse developmental abnormalities are also noted. A majority of patients with DBA respond to steroid therapy. Recent molecular studies have identified mutations in the gene encoding the ribosomal protein RPS19 on chromosome 19 in 25% of patients with DBA. In another subset of patients, linkage analysis has identified another locus on chromosome 8p in association with DBA. There are, however, other cases of DBA that are linked neither to the RPS19 gene nor to the locus on 8p, implying the involvement of yet-to-be-defined genetic defects in the cause of DBA. The pathogenesis of DBA is still to be fully defined and it is anticipated that further molecular studies will lead to a better understanding of this complex disease.