Human Molecular Genetics, Vol 7, 2073-2078, Copyright © 1998 by Oxford University Press
RE Ferrell, KL Levinson, JH Esman, MA Kimak, EC Lawrence, MM Barmada and DN Finegold
Hereditary or primary lymphedema is a developmental disorder of the
lymphatic system which leads to a disabling and disfiguring swelling of the
extremities. Hereditary lymphedema generally shows an autosomal dominant
pattern of inheritance with reduced penetrance, variable expression and
variable age at onset. Three multigeneration families demonstrating the
phenotype of hereditary lymphedema segregating as an autosomal dominant
trait with incomplete penetrance were genotyped for 366 autosomal markers.
Linkage analysis yielded a two-point LOD score of 6.1 at straight theta =
0. 0 for marker D5S1354 and a maximum multipoint LOD score of 8.8 at marker
D5S1354 located at chromosome 5q34-q35. Linkage analysis in two additional
families using markers from the linked region showed one family consistent
for linkage to distal chromosome 5. In the second family, linkage to 5q was
excluded for all markers in the region with LOD scores Z < -2.0. The
vascular endothelial growth factor C receptor ( FLT4 ) was mapped to the
linked region, and partial sequence analysis identified a G-->A
transition at nucleotide position 3360 of the FLT4 cDNA, predicting a
leucine for proline substitution at residue 1126 of the mature receptor in
one nuclear family. This study localizes a gene for primary lymphedema to
distal chromosome 5q, identifies a plausible candidate gene in the linked
region, and provides evidence for a second, unlinked locus for primary
lymphedema.
ARTICLES
Hereditary lymphedema: evidence for linkage and genetic heterogeneity
Departments of Human Genetics, Physical Medicine and Rehabilitation and Pediatrics, University of Pittsburgh, 130 DeSoto Street, Pittsburgh, PA 15261, USA.
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