Thorax 2000;55:685-690 ( August )

A hereditary haemorrhagic telangiectasia family with pulmonary involvement is unlinked to the known HHT genes, endoglin and ALK-1

G M F Wallace^a, C L Shovlin^b

^a Rayne Laboratories, Respiratory Medicine, University of Edinburgh, Edinburgh, UK, ^b Respiratory Medicine, Imperial College School of Medicine, National Heart and Lung Institute, Hammersmith Hospital, London W12 0NN, UK

Correspondence to: Dr C L Shovlin email: c.shovlin{at}ic.ac.uk

Received 6 December 1999; Returned to authors 21 February 2000; Revised version received 18 April 2000; Accepted for publication 18 April 2000

BACKGROUNDPulmonary arteriovenous malformations (PAVMs) occur in over 25% of patients with the autosomal dominant disorder hereditary haemorrhagic telangiectasia (HHT). Mutations in two genes, endoglin and ALK-1, are known to cause HHT. Each encodes a protein expressed on vascular endothelial cells and involved in signalling by members of the transforming growth factor (TGF)- superfamily. To date, PAVMs have not been detected in ALK-1 families. There is evidence from a single HHT family without pulmonary involvement that a third HHT gene may exist. To establish the existence of a further HHT gene responsible for PAVMs, linkage analyses were performed on an expanded PAVM-HHT family in which HHT did not result from endoglin mutations.
METHODSFamily members were assessed clinically to assign HHT disease status and were screened for PAVMs. DNA was extracted from blood obtained from 20 individuals of known disease status. Short tandem repeat polymorphic markers spanning the intervals containing the endoglin and ALK-1 genes were amplified by the polymerase chain reaction using ³³P-labelled oligonucleotide primers, separated by denaturing polyacrylamide gel electrophoresis (PAGE), and the resultant autoradiographs were examined for allele sizes. Linkage analyses were performed using MLINK and GENEHUNTER.
RESULTSTwelve members spanning four generations were affected with HHT. Two had proven PAVMs, one with a classical appearance, the other exhibiting microscopic PAVMs exacerbated by pregnancy. Two point lod and multipoint lod scores significantly excluded linkage to endoglin and ALK-1 in this pedigree.
CONCLUSIONSThis study confirms the existence of a third HHT locus that accounts for disease in some HHT patients with pulmonary involvement.


Keywords: genetic linkage; pulmonary arteriovenous malformations; transforming growth factor

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© 2000 by Thorax
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