PMID- 10545596
OWN - NLM
STAT- MEDLINE
DCOM- 19991214
LR  - 20190513
IS  - 0964-6906 (Print)
IS  - 0964-6906 (Linking)
VI  - 8
IP  - 12
DP  - 1999 Nov
TI  - Expression analysis of four endoglin missense mutations suggests that
      haploinsufficiency is the predominant mechanism for hereditary hemorrhagic
      telangiectasia type 1.
PG  - 2171-81
AB  - ENDOGLIN codes for a homodimeric membrane glycoprotein that interacts with
      receptors for members of the TGF-beta superfamily and is the gene mutated in the 
      autosomal dominant vascular disorder hereditary hemorrhagic telangiectasia type 1
      (HHT1). We recently demonstrated that functional endoglin was expressed at half
      levels on human umbilical vein endothelial cells (HUVECs) and peripheral blood
      activated monocytes from HHT1 patients. Two types of mutant protein were
      previously analyzed, the product of an exon 3 skip which was expressed as a
      transient intracellular species and prematurely truncated proteins that were
      undetectable in patient samples. Here we report the analysis of four proteins
      resulting from point mutations, with missense codons G52V and C53R in exon 2,
      W149C in exon 4 and L221P in exon 5. Metabolic labeling of activated monocytes
      from confirmed, clinically affected patients revealed reduced expression of fully
      processed normal endoglin in all cases. Pulse-chase analysis with HUVECs from a
      newborn with the C53R substitution indicated that mutant endoglin remained
      intracellular as a precursor form and did not impair processing of the normal
      protein. Biotinylation of cell surface proteins, metabolic labeling and
      pulse-chase analysis revealed that none of the engineered missense mutants was
      significantly expressed at the surface of COS-1 transfectants. Thus, these four
      HHT1 missense mutations lead to transient intracellular species which cannot
      interfere with normal endoglin function. These data suggest that
      haploinsufficiency, leading to reduced levels of one of the major surface
      glyco-proteins of vascular endothelium, is the predominant mechanism underlying
      the HHT1 phenotype.
FAU - Pece-Barbara, N
AU  - Pece-Barbara N
AD  - Cancer and Blood Research Programme, Hospital for Sick Children and Department of
      Immunology, University of Toronto, 555 University Avenue, Toronto M5G 1X8,
      Canada.
FAU - Cymerman, U
AU  - Cymerman U
FAU - Vera, S
AU  - Vera S
FAU - Marchuk, D A
AU  - Marchuk DA
FAU - Letarte, M
AU  - Letarte M
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Hum Mol Genet
JT  - Human molecular genetics
JID - 9208958
RN  - 0 (Antigens, CD)
RN  - 0 (DNA Primers)
RN  - 0 (ENG protein, human)
RN  - 0 (Endoglin)
RN  - 0 (Receptors, Cell Surface)
RN  - 0 (Vascular Cell Adhesion Molecule-1)
SB  - IM
MH  - Animals
MH  - Antigens, CD
MH  - Base Sequence
MH  - COS Cells
MH  - Cell Line
MH  - Cell Membrane/metabolism
MH  - DNA Primers
MH  - Endoglin
MH  - Haplotypes
MH  - Humans
MH  - *Mutation, Missense
MH  - Receptors, Cell Surface
MH  - Telangiectasia, Hereditary Hemorrhagic/*genetics
MH  - Vascular Cell Adhesion Molecule-1/*genetics
EDAT- 1999/11/05 00:00
MHDA- 1999/11/05 00:01
CRDT- 1999/11/05 00:00
PHST- 1999/11/05 00:00 [pubmed]
PHST- 1999/11/05 00:01 [medline]
PHST- 1999/11/05 00:00 [entrez]
AID - ddc248 [pii]
AID - 10.1093/hmg/8.12.2171 [doi]
PST - ppublish
SO  - Hum Mol Genet. 1999 Nov;8(12):2171-81. doi: 10.1093/hmg/8.12.2171.