title: RNA and protein evidence for haplo-insufficiency in Diamond-Blackfan anaemia patients with RPS19 mutations.
abstract: 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.
authors.affiliation: Department of Pediatric Oncology, Dana Farber Cancer Institute, Boston, MA 02115, USA. hanna_gazda@dfci.harvard.edu
authors.forename: Hanna T
authors.initials: HT
authors.lastname: Gazda
authors.forename: Rong
authors.initials: R
authors.lastname: Zhong
authors.forename: Lilia
authors.initials: L
authors.lastname: Long
authors.forename: Edyta
authors.initials: E
authors.lastname: Niewiadomska
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Lipton
authors.forename: Anna
authors.initials: A
authors.lastname: Ploszynska
authors.forename: Jan M
authors.initials: JM
authors.lastname: Zaucha
authors.forename: Adrianna
authors.initials: A
authors.lastname: Vlachos
authors.forename: Evangelia
authors.initials: E
authors.lastname: Atsidaftos
authors.forename: David H
authors.initials: DH
authors.lastname: Viskochil
authors.forename: Charlotte M
authors.initials: CM
authors.lastname: Niemeyer
authors.forename: Joerg J
authors.initials: JJ
authors.lastname: Meerpohl
authors.forename: Roma
authors.initials: R
authors.lastname: Rokicka-Milewska
authors.forename: Dagmar
authors.initials: D
authors.lastname: Pospisilova
authors.forename: W
authors.initials: W
authors.lastname: Wiktor-Jedrzejczak
authors.forename: David G
authors.initials: DG
authors.lastname: Nathan
authors.forename: Alan H
authors.initials: AH
authors.lastname: Beggs
authors.forename: Colin A
authors.initials: CA
authors.lastname: Sieff
mesh_terms: 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
chemical_list: D018952:Antigens, CD34; D018076:DNA, Complementary; D012333:RNA, Messenger; D012269:Ribosomal Proteins; C040343:ribosomal protein S19