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RED CELLS
From the Division of Pediatric Hematology and Oncology,
Dana Farber Cancer Institute and Children's Hospital, Division of
Genetics, Children's Hospital and Department of Pediatrics, Harvard
Medical School, Boston, Massachusetts; Division of Pediatric
Hematology/Oncology, Mount Sinai School of Medicine, New York, New
York; Department of Hematology, Hôpital Bicêtre, Assitance
Publique-Hôpitaux de Paris et Faculte de Médicine, Paris,
France; Lawrence Berkeley National Laboratory, Berkeley, California;
Department of Haematology, St. George's Hospital Medical School,
London, England; Children's Hospital, University of Freiburg, Germany;
Whitehead Institute for Biomedical Research, Massachusetts Institute of
Technology, Cambridge, Massachusetts; Department of Pediatric
Hematology and Oncology, University of Gdansk, Poland; Division of
Pediatric Hematology/Oncology, Stanford University School of Medicine,
Stanford, California; Department of Pediatric Hematology/Oncology,
Warsaw School of Medicine, Warsaw, Poland; Department of Pediatrics,
Toho University School of Medicine, Tokyo, Japan; Department of
Pediatric Haematology/Oncology, Princess Margaret Hospital for
Children, Perth, Australia; Department of Pediatrics, University
Hospital, Olomouc, Czech Republic; Division of Medical Genetics,
University of Utah School of Medicine, Salt Lake City, UT.
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 (DBA) is a rare congenital
hypoplastic anemia that usually presents early in infancy. The disease is characterized by a moderate to severe normochromic, often macrocytic anemia, reticulocytopenia, and selective erythroblastopenia in the bone
marrow.1,2 Although most cases are apparently sporadic, 10% to 20% show clear patterns of inheritance, most commonly
autosomal dominant.1 DBA is markedly heterogeneous
clinically, and within affected families anemia may be mild or absent
in some individuals, with only subtle indications of the erythroid
abnormality such as increased mean corpuscular volume (MCV) or
erythrocyte adenosine deaminase activity (eADA) or both.3
More than 40% of patients have congenital abnormalities, particularly
of the upper limb and craniofacial regions.1,4-6 Recently,
linkage analysis of 29 European families showed that DBA in 26 of both
dominant and recessive families mapped to chromosome 19q.7
Identification of a patient with a translocation led to the cloning of
a gene on chromosome 19q13.2 that encodes a ribosomal protein,
RPS19.8,9 However, mutations of the RPS19 gene
have only been identified in 25% of cases,8,10 suggesting
a greater degree of genetic heterogeneity than expected from the
initial linkage studies.7,11 In this report we provide
evidence for the existence of a second DBA gene on
chromosome 8p, and also for further genetic heterogeneity.
Patients
The affection status of each family member was determined by the
primary hematologist in the country of origin and confirmed by our
review of the clinical and laboratory data. Diagnosis was based on
accepted criteria for DBA, namely, normochromic anemia in infancy or
early childhood, reticulocytopenia, normal leukocyte and platelet
counts, and decreased to absent bone marrow erythroid precursors. One
family (P18; Figure 1) had 2 affected members with typical DBA
phenotype, but normal bone marrow erythropoiesis, as described in 5%
of cases.1 All members of the DBA families were examined
for congenital malformations and macrocytosis; eADA and hemoglobin
F (HbF) were determined in most but not all families.
Diamond-Blackfan anemia is markedly heterogeneous with respect to the
presence or absence of congenital abnormalities, the response to
treatment, and evolution of the disease over time. Moreover, within
families containing individuals with typical DBA, silent or mild
expressions of the disease such as mild anemia or increased MCV or eADA
or both have been reported in apparently unaffected family
members3; indeed, in some families the RPS19 mutation cosegregates with affected individuals and with other family
members who are macrocytic or in whom eADA is elevated more than 3 SDs
above the mean value.10 On clinical grounds we
distinguished 2 different types of kindreds among all the multiplex DBA
families. The majority of families comprised 2 or more affected individuals who presented with classical DBA with anemia,
reticulocytopenia, and erythroblastopenia in the bone marrow.
Coexistence of mild and severe forms of anemia in 3 families (P16, P23,
and P34; Figure 1) was observed. The individuals who presented with
mild anemia in these pedigrees were coded as affected in the linkage
study, because they were offspring/siblings and parents of severely
affected patients. Moreover, in one pedigree (P23; Figure 1), 5 affected individuals, including the member with mild anemia, presented with increased MCV (macrocytosis) and elevated eADA. This family has
been described elsewhere.12 A second group of 12 pedigrees (P14, 15, 17, 18, 22, 30, 37, 39, 43, 45, 48, 49; Figure 1) comprised classically affected probands and one or 2 individuals who presented with normal or slightly decreased hemoglobin level but with unexplained macrocytosis or highly elevated eADA or both, more then 3 SD above the
mean value. These individuals were designated as genetically affected
with variable expressivity of the phenotype.3 A number of
affected individuals in both groups presented with various congenital
malformations such as webbed neck, thumb abnormalities, congenital
heart defect, urogenital malformations, and short stature. In one
patient mild mental retardation was present. Family members were
designated as unaffected if they had normal red blood cell counts, no
congenital malformations, and did not have an unexplained elevated eADA
or MCV. Thirty-two families manifested autosomal dominant inheritance;
6 pedigrees (P21, 32, 38, 44, 45, 47; Figure 1) with 2 severely
affected children had parents with no clinical or laboratory signs of
anemia and could represent either autosomal dominant inheritance with
incomplete penetrance, gonadal mosaicism for a dominant mutation in one
of the parents, or autosomal recessive inheritance. The paternity in
these families was confirmed by extended haplotype analysis. The
affection status of unaffected individuals in these families was coded
as unknown.
DNA genotyping
RPS19 gene sequencing
Statistical analysis The GENEHUNTER program (version 1.1) was used for parametric 2- and multipoint LOD score calculation16 with the assumption of autosomal dominant pattern of inheritance. Varied penetrance values were used (0.7, 0.8, 0.85, 0.9, and 0.95), with an assumed disease-gene frequency of 0.000001 (that is, disease incidence 2/1 000 000 births) and no sex difference with reference to disease frequency. Changing the disease gene frequency by several orders of magnitude had minimal influence on the results. The allele frequencies for each polymorphism, locus order, and the genetic and physical distances between them were obtained from GDB, NCBI (http://www.ncbi.nlm.nih.gov/) and Généthon.
Chromosome 19q linkage The PCR primers were used to amplify polymorphic markers on chromosome 19q13.2 (D19S197, LIPE, D19S408, D19S178) known to be linked to the DBA phenotype.7 RPS19 is located between D19S197 and LIPE.8 Haplotype data for 5 of 14 initially studied families (Table 1) were consistent with linkage to chromosome 19q13.2 (P5, 7, 8, 10, 14; Figure 1). Haplotype analysis performed in the other 9 families (P1, 2, 4, 11, 15, 16, 17, 18, 19; Figure 1, Table 1) were not consistent with linkage to this region.
Genomewide screen and linkage to chromosome 8p Because these data indicated that the locus on chromosome 19q did not explain many of our cases, a genome-wide search was performed for linked loci in all 14 pedigrees. Haplotype analysis revealed a subgroup of 8 pedigrees consistent with linkage to chromosome 8p (P1, 2, 4, 5, 11, 14, 17, 18; Figure 1); 6 pedigrees were not consistent with linkage to this region (P7, 8, 10, 15, 16, 19; Figure 1). Two of 8 families consistent with linkage to chromosome 8p were also consistent with linkage to chromosome 19q (P5, 14; Figure 1). The genome-wide search showed the highest number of pedigrees consistent with linkage to chromosome 8p, suggesting the possibility of a second DBA gene in that region. However, the result was inconclusive because of the relatively small size and number of families studied.To address this issue, we ascertained 24 additional pedigrees (P20-49; Figure 1), and, together with the first subset of 14 families, thus analyzed 38 pedigrees in total. Eighteen of 38 families were consistent with linkage to 8p, 14 families were inconsistent, and 6 families did not show vertical transmission of the disease; it is thus difficult to assess linkage to this region in these 6 families (Table 1). They may represent autosomal dominant inheritance with reduced penetrance, mosaicism, germline mutation in one of the parents, or an autosomal recessive pattern of inheritance. RPS19 gene mutations Twelve of 38 pedigrees were consistent with linkage to chromosome 19q, 19 were inconsistent with linkage to this region, and results of linkage analysis of 7 pedigrees were inconclusive (Figure 1, Table 1). Subsequent sequence analysis of the RPS19 gene in affected individuals from all 38 families revealed different missense mutations in 3 families. One of them is a novel mutation located in exon 5 at codon 131 (T392G; Leu Arg) in pedigree P14. Two other
mutations, detected in exon 3 at codon 56 (G167A; Arg Gln) in
P38, and in exon 4 at codon 62 (G185A; Arg Gln) in affected individuals from pedigree P23 (Figure 1, Table 1), were previously described.10,17 No other mutations were found in the 6 exons or their flanking regions in the other 35 pedigrees.
Multipoint linkage analysis with heterogeneity Because the high degree of genetic heterogeneity and small family size precluded unambiguous identification of the subset of families with the second DBA locus we used the GENEHUNTER program to analyze all studied families except the 3 with mutations in exons 3, 4, and 5 of the RPS19 gene, giving a total of 35 families. The parametric multipoint LOD score with heterogeneity (HLOD score), varied between 3.33 and 3.59 at penetrance 0.7 to 0.95 for marker D8S277, with the proportion ( ) of families linked to the locus equal to 0.56 to
0.48 (Table 2, Figure
2). In other words we estimate from our
data that approximately 50% of families are consistent with linkage to
the region of 8p with the highest HLOD score. The HLOD score decreases
to 0.64 and 0.735 for locus D8S1145 at penetrances 0.7 to 0.95 (Table
2, Figure 2), suggesting strongly that the gene resides telomeric to
this marker. These results provide evidence for a second DBA
gene in the 26.4-cM interval of human chromosome 8p23.3-p22.
Evidence for non-19q non-8p DBA In total, haplotype analysis did not reveal linkage of DBA to chromosome 8p in 14 of the 38 families (P7, 8, 10, 15, 16, 19, 20, 22, 23, 25, 27, 41, 42, 49; Figure 1, Table 1). Seven of these families also showed no evidence for linkage to chromosome 19q (P15, 16, 19, 22, 27, 42, 49); all of them were negative for RPS19 mutations (Table 1) by sequencing. Thus, data on 7 pedigrees support the existence of a non-19q non-8p gene (or genes). In 3 of these families haplotype segregation provided strong evidence for non-19q non-8p DBA gene location (P22, 27, 49) in that discordance of 19q and 8p haplotypes was found in affected family members.
Our data suggest that a second gene for DBA resides in the telomeric region of human chromosome 8p23.3-p22. Statistical analysis revealed significant HLOD scores for the telomeric region of the chromosome 8p markers flanked by D8S1145 at penetrance 0.7 and higher. Estimation of the disease gene penetrance in DBA is difficult because of the high degree of clinical heterogeneity in this disease; however, using the single ascertainment approach18 in pedigrees that show vertical disease transmission we calculated that the disease penetrance is approximately 0.9. This result supports the significance of the HLOD score calculated at a penetrance of 0.9 (Figure 2). Additionally we found recombinations in affected individuals in 5 of the 8p-linked families (P1, 4, 11, 17, 43) within that region. Recombinations in pedigrees P17 and P43 occurred with marker D8S518, in families P1 and P4 with D8S1145, and in pedigree P11 with marker D8S1825, suggesting that the potential critical region is flanked by the polymorphic markers D8S518 and D8S1825. These data suggested that the second DBA gene is possibly located within an 8.1-cM interval that contains approximately 1.89 Mb DNA and maps to chromosome 8p23.2-p23.1 (GDB html as above). In total, haplotype analysis identified 18 families that were consistent with linkage to an 8p locus. Two of these families (P17, 18) include both severely affected members and individuals with only an increased MCV (> 3 SD above mean value) but no history of anemia. Unexplained macrocytosis in DBA kindreds in which clinically affected members also have an increased MCV suggests strongly that macrocytic individuals carry a DBA gene mutation and have variable expressivity of the phenotype. Variable expressivity was described in 2 families each with 2 clinically affected half-siblings and an unaffected common parent, who was therefore an obligatory gene carrier; the parent in each family had no symptoms of anemia, but did have an elevated MCV and HbF.19,20 Moreover, Willig et al reported a family with an RPS19 mutation in individuals with classical DBA and in a clinically unaffected father who presented only with macrocytosis.10 In addition to the chromosome 8p- and 19q-linked families, we found 7 pedigrees inconsistent with linkage to either 8p or 19q, and negative for RPS19 gene mutations (P15, 16, 19, 22, 27, 42, 49). In 4 of these, (P15, 16, 19, 42), possible explanations for this finding could be either genetic heterogeneity or lack of penetrance of the disorder in healthy siblings. However, in 3 families (P22, 27, 49) the segregation of 2 different haplotypes of chromosome 19q and 8p in affected family members provided strong evidence for a non-19q non-8p locus. We found that the 19q families, the 8p families, and the non-8p non-19q families all contained pedigrees with the classical severe DBA phenotype as well as families with severe and mild anemia. Moreover, some individuals from each group had increased MCV or elevated eADA or both, that is, variable expressivity of the phenotype. Thus, with the proviso that insufficient families have been studied, our data do not show any correlations between clinical phenotype and genotype at this time. Examination of candidate genes that map to the critical interval reveal
no ribosomal protein genes known to map to 8p23.3-p22 region.
Seventy-five of the 80 known mammalian ribosomal protein genes have
been mapped,21 so it is possible that one of the 5 unmapped genes will localize to chromosome 8p. The region does not
contain any obvious candidates, but one gene, GATA4,
warrants discussion. GATA4 is expressed during embryogenesis
in extraembryonic visceral endoderm and appears to play an indirect
role in the development of the primitive hemangioblasts that give rise
to both endothelial and hematopoietic cells within blood islands of the
yolk sac22-24; it is also thought to be important in
cardiac development. Targeted disruption of GATA4 in mice is
embryonic lethal,23,24 but
GATA4 In conclusion, we provide strong evidence for genetic heterogeneity of DBA. Our data indicate the existence of a second DBA gene on chromosome 8p23.3-p22, most likely within an 8.1-cM interval that contains approximately 1.89 Mb DNA and maps to chromosome 8p23.2-p23.1. Our results also indicate further genetic heterogeneity; that is, there is likely at least one more DBA gene in addition to those on chromosomes 19q and 8p. However, the high degree of genetic heterogeneity makes it difficult to generate statistical proof concerning the latter point. Confirmation of an 8p DBA locus will need to await the results of follow-up studies in additional patient populations as well as mutation studies of candidate genes in the region. The genetic data raise the possibility that proteins encoded by the different DBA genes interact in a common and novel pathway that affects erythropoiesis and other specific aspects of development.
Submitted June 19, 2000; accepted November 22, 2000.
Supported by grants from the Daniella Maria Arturi Foundation, the Diamond Blackfan Anemia Foundation, the Association Française contre les Myopathies, Généthon, National Institutes of Health (NIH) AR44345, DK 26263, Direction de la Recherche Clinique (CRC 95183) and the Max Reinhardt Charitable Trust. H.G. was supported by F05 TW05395 from the Fogarty International Center, NIH, and A.H.B. by NIH KO2 award AR02026.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Hanna Gazda, Pediatric Oncology, Rm M615, Dana Farber Cancer Institute, 44 Binney St, Boston, MA 02115.
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Abstract
Introduction
/