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Chapter 29 Inherited Bone Marrow Failure Syndromes 373

DBA genes are components of the small or large ribosome subunits. depletion of RPL35A reduces the amount of the 60S subunit and of
Except for the rare cases with mutations in GATA1, all genetically the mature 80S ribosomes.
proven cases show autosomal dominant inheritance with variable The mechanism by which ribosomal protein gene mutations
penetrance. Recessive inheritance was inferred in more than 30 impairs RBC development remains unknown. In 25% of cases with
families published in the literature that had affected siblings with mutant RPS19, the prevailing opinion is that the disorder results from
normal parents, affected cousins, or consanguinity. However, these protein haploinsufficiency. In support of this, two classes of RPS19
cases have not been confirmed as autosomal recessive. Some of these mutations have been described: quantitative defects resulting in
may be autosomal dominant with partial penetrance or arise from undetectable protein and hotspot mutations leading to loss of func-
gonadal mosaicism. tion. Additional links between RPS19 and erythropoiesis have now
been clearly established. Defective erythropoiesis ensues when RPS19
is knocked down in cellular models. In addition, wild-type gene
Epidemiology transfer corrects the defective erythropoiesis in RPS19-deficient DBA
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CD34 cells resulting in a threefold increase in erythroid colony
Based on data from a European registry of DBA patients, the esti- growth. In yeast, the introduction of RPS19 mutations found in DBA
mated incidence of the disorder as assessed for France over a 13-year results in a defect in the processing of pre-rRNA similar to that
period was 7.3 cases per million live births. Data from the CIMFR observed in DBA cells with decreased expression of RPS19.
show an incidence of 10.4 cases per million live births as assessed A large body of evidence indicates that the erythroid progenitor
over a 9-year period. Although the majority of published patients are compartment is intrinsically defective in DBA. A study from England
white, DBA has been recognized in several ethnic groups, including showed that the frequency and clonogenicity of DBA early erythroid
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+
−
−
African blacks, Arabs, East Indians, and Japanese. progenitors (defined by LinCD34 CD38 CD45RA CD123 CD71 +
−
−
−
In terms of gender distribution, both sexes are equally affected. CD41a CD105 CD36 ) and late erythroid progenitors (as defined
−
+
−
−
+/−
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About 80% of DBA cases are sporadic. by Lin CD34 CD38 CD45RACD123 CD71 CD41a CD105
+ CD36+) are significantly decreased in DBA. Standard clonogenic
assays for CFU-E and BFU-E progenitors consistently have shown
Genetics reduced or absent colonies in most DBA patients and intermediate,
normal, or occasionally increased numbers in the rest. The DBA
The discovery of 16 DBA genes (see Table 29.1) demonstrates het- erythroid progenitors are relatively insensitive to erythropoietin in
erozygosity for mutations in the respective genes consistent with vitro and to burst-promoting activity, but the hyporesponsiveness to
autosomal dominant inheritance in most currently known genetic erythropoietin can be corrected in some cases by the addition of
groups. Except for GATA1, all known DBA proteins are structural glucocorticoids in vitro or by clinically administering prednisone.
components of either the small or large ribosomal subunits. The data underscore the fact that the intrinsic defect of DBA
In most DBA cases peripheral blood karyotype is normal. Discov- erythroid progenitors is an inability to respond normally to inducers
ery of a balanced reciprocal translocation t(x;19) in a sporadic female of erythroid proliferation, differentiation, or both. Indeed, DBA
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case of DBA and the identification of microdeletions on chromosome CD34 HSCs/early progenitors differentiate normally along mega-
19 in some other DBA patients led to the identification of the first karyocytic and granulocytic pathways in short-term cultures but
DBA gene mutation. Subsequent studies revealed mutations in one aberrantly along the erythroid lineage. Accelerated programmed cell
allele for the gene in 25% of patients, and it is currently the most death (apoptosis) plays a central role in this pathogenesis as it does
common known mutant DBA gene. in many, if not all, inherited BM failure disorders. A role for induc-
RPS19 protein is a component of the ribosomal 40S subunit. tion of apoptosis by the Fas–Fas ligand system in DBA was suggested
Multiple other genes encoding either the 40S small ribosome subunit because of elevated serum soluble Fas ligand in patients compared
or 60S ribosome subunit have been subsequently identified in DBA. with control participants. Based on the various patterns of erythroid
The second most commonly mutated gene in DBA is RPL5. It is colony growth seen with DBA patients, a model for the aberrant
mutated in 12% to 21% of patients. Other mutated genes are RPL11 erythropoiesis was developed that proposes maturational arrest at
(7–9% of patients), RPS26 (10%), RPS10 (4%), RPS24 (2%), varying sites along the differentiation pathway.
RPL35a (2%), RPS17 (<1%), and RPS7 (<1%). About 70% of The combination of recombinant IL-3 and stem cell factor (SCF)
patients with DBA can now be genotyped. increases the in vitro clonogenicity of DBA BM progenitors. The size
It is important to note that about 20% of patients with DBA have and number of DBA BFU-E colonies are dramatically increased. The
large deletion in one of the DBA genes rather than nucleotide-level data on the effect of IL3, SCF, or GM-CSF as single agents is less
mutations. Therefore metaphase cytogenetics and molecular karyo- conclusive. The human ligand for flt-3 apparently has no effect on
typing to detect microscopic and submicroscopic deletions, respec- DBA BM colony growth. However, addition of IL-9 to SCF, IL-3,
tively, should be included in the genetic testing process if the and erythropoietin does potentiate DBA BFU-E growth.
sequencing of known DBA gene is negative. There are significant age-related changes in erythroid and granu-
lopoietic progenitors in DBA patients. Despite profound anemia,
seven of 10 patients studied within 1 year of diagnosis had normal
Pathophysiology numbers of CFU-E and BFU-E that showed a normal response to
cytokines. In contrast, 12 of 14 patients followed for more than 3
Recent studies have shed light on the function of the RPS19 protein years had decreased erythroid progenitors and, in 7 cases, decreased
in ribosome biogenesis. RPS19 associates with the ribosomal subunit CFU-GM. The data are consistent with the idea that the DBA defect
40S. It is critical for normal maturation of rRNA because its defi- involves other hematopoietic lineages and worsens with time.
ciency causes defective cleavage of the pre-rRNA at the ITS1 sequence Strong support for this conclusion comes from a detailed study
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and abnormal maturation of the 40S subunit. This leads to accumula- that examined the interaction between DBA CD34 cells and the
tion of faulty pre-40S ribosome subunits. hematopoietic microenvironment using long-term BM cultures.
Other ribosomal proteins that are mutated in DBA are also critical Stromal adherent layers from DBA patients did not show evidence
for ribosome biogenesis, For example, it has been shown that the yeast of any morphologic, phenotypic, or functional abnormality, and the
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RPL11 is positioned at the intersubunit cleft of the large ribosome stroma sustained the proliferation of normal CD34 cells. A major
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subunit central protuberance, thereby forming an intersubunit bridge finding was an impaired capacity of DBA CD34 cells in the presence
with the small subunit protein S18. Mutations in this region such as of normal stromal cells to proliferate and differentiate along not only
F96 and A66 lead to halfmer formation. Mutations in RPS24 also the erythroid pathway but also along the granulocytic–macrophage
impair pre-rRNA processing of the 18S rRNA and decrease the pathway. These results indicate an intrinsic defect of a hematopoietic
production of the 40S ribosomal subunit. On the other hand, progenitor with at least bilineage potential that places it earlier than