MYH9 spectrum of autosomal-dominant giant platelet syndromes: unexpected association with fibulin-1 variant-D inactivation.
The autosomal-dominant giant platelet syndromes (Fechtner, Epstein, and Sebastian platelet syndromes and May-Hegglin anomaly) represent a group of disorders characterized by variable degrees of macrothrombocytopenia with further combinations of neutrophil inclusion bodies and Alport-like syndrome manifestations, namely, deafness, renal disease, and eye abnormalities. The disease-causing gene of these giant platelet syndromes was previously mapped by us to chromosome 22. Following their successful mapping, these syndromes were shown to represent a broad phenotypic spectrum of disorders caused by different mutations in the nonmuscle myosin heavy chain 9 gene (MYH9). In this study, we examined the potential role of another gene, fibulin-1, encoding an extracellular matrix protein as a disease modifier. Eight unrelated families with autosomal-dominant giant platelet syndromes were studied for DNA sequence mutations and expression of the four fibulin-1 splice variants (A-D). A mutation in the splice acceptor site of fibulin-1 exon 19 was found in affected individuals of the Israeli Fechtner family, whereas no MYH9 mutations were identified. Unexpectedly, fibulin-1 variant D expression was absent in affected individuals from all eight families and coupled with expression of a putative antisense RNA. Transfection of the putative antisense RNA into H1299 cells abolished variant D expression. Based on the observation that only affected individuals lack variant D expression and demonstrate antisense RNA overexpression, we suggest that these autosomal-dominant giant platelet syndromes are associated, and may be modified, by aberrant antisense gene regulation of the fibulin-1 gene.
Toren
Amos
A
Pediatric Hemato-Oncology Department and the Institute of Hematology, the Chaim Sheba Medical Center, Tel-Hashomer, Tel-Aviv University, Israel. amost@post.tau.ac.il
Rozenfeld-Granot
Galit
G
Heath
Karen E
KE
Amariglio
Ninette
N
Rocca
Bianca
B
Crosson
John
J
Epstein
Charles J
CJ
Laghi
Ferdinando
F
Landolfi
Raffaele
R
Carlsson
Lena E
LE
Argraves
Scott
S
Bizzaro
Nicola
N
Moxey-Mims
Marva
M
Brok-Simoni
Frida
F
Martignetti
John A
JA
Greinacher
Andreas
A
Rechavi
Gideon
G
D001483:Base Sequence; D001606:Bernard-Soulier Syndrome / Q000209:etiology / Q000235:genetics*; D002135:Calcium-Binding Proteins / Q000235:genetics*; D004252:DNA Mutational Analysis; D005192:Family Health; D020868:Gene Silencing; D005799:Genes, Dominant; D006801:Humans; D020409:Molecular Motor Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D009154:Mutation; D018995:Myosin Heavy Chains / Q000235:genetics*; D020033:Protein Isoforms / Q000235:genetics; D034622:RNA Interference; D022821:RNA Splice Sites / Q000235:genetics; D016372:RNA, Antisense / Q000032:analysis / Q000096:biosynthesis / Q000502:physiology
D002135:Calcium-Binding Proteins; C103814:MYH9 protein, human; D020409:Molecular Motor Proteins; D020033:Protein Isoforms; D022821:RNA Splice Sites; D016372:RNA, Antisense; C060820:fibulin; D018995:Myosin Heavy Chains