RNA and protein evidence for haplo-insufficiency in Diamond-Blackfan anaemia patients with RPS19 mutations.
The genetic basis of Diamond-Blackfan anaemia (DBA), a congenital erythroid hypoplasia that shows marked clinical heterogeneity, remains obscure. However, the fact that nearly one-quarter of patients harbour a variety of mutations in RPS19, a ribosomal protein gene, provides an opportunity to examine whether haplo-insufficiency of RPS19 protein can be demonstrated in certain cases. To that end, we identified 19 of 81 DBA index cases, both familial and sporadic, with RPS19 mutations. We found 14 distinct insertions, deletions, missense, nonsense and splice site mutations in the 19 probands, and studied mutations in 10 patients at the RNA level and in three patients at the protein level. Characterization of the mutations in 10 probands, including six with novel insertions, nonsense and splice site mutations, showed that the abnormal transcript was detectable in nine cases. The RPS19 mRNA and protein in CD34+ bone marrow cells identified haplo-insufficiency in three cases predicted to have one functional allele. Our data support the notion that, in addition to rare DBA patients with the deletion of one allele, the disease in certain other RPS19 mutant patients is because of RPS19 protein haplo-insufficiency.
Gazda
Hanna T
HT
Department of Pediatric Oncology, Dana Farber Cancer Institute, Boston, MA 02115, USA. hanna_gazda@dfci.harvard.edu
Zhong
Rong
R
Long
Lilia
L
Niewiadomska
Edyta
E
Lipton
Jeffrey M
JM
Ploszynska
Anna
A
Zaucha
Jan M
JM
Vlachos
Adrianna
A
Atsidaftos
Evangelia
E
Viskochil
David H
DH
Niemeyer
Charlotte M
CM
Meerpohl
Joerg J
JJ
Rokicka-Milewska
Roma
R
Pospisilova
Dagmar
D
Wiktor-Jedrzejczak
W
W
Nathan
David G
DG
Beggs
Alan H
AH
Sieff
Colin A
CA
D029503:Anemia, Diamond-Blackfan / Q000235:genetics* / Q000378:metabolism; D018952:Antigens, CD34 / Q000032:analysis; D001854:Bone Marrow Cells / Q000378:metabolism; D004252:DNA Mutational Analysis / Q000379:methods; D018076:DNA, Complementary / Q000235:genetics; D006239:Haplotypes; D006801:Humans; D009154:Mutation; D010375:Pedigree; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D012269:Ribosomal Proteins / Q000235:genetics* / Q000378:metabolism
D018952:Antigens, CD34; D018076:DNA, Complementary; D012333:RNA, Messenger; D012269:Ribosomal Proteins; C040343:ribosomal protein S19