Premium
FLT 4 / VEGFR 3 and M ilroy Disease: Novel Mutations, a Review of Published Variants and Database Update
Author(s) -
Gordon Kristiana,
Spiden Sarah L.,
Connell Fiona C.,
Brice Glen,
Cottrell Sally,
Short John,
Taylor Rohan,
Jeffery Steve,
Mortimer Peter S.,
Mansour Sahar,
Ostergaard Pia
Publication year - 2013
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22223
Subject(s) - biology , penetrance , missense mutation , genetics , lymphedema , locus (genetics) , phenotype , gene , exome , lymphangiogenesis , genotype , haploinsufficiency , database , bioinformatics , exome sequencing , cancer , metastasis , breast cancer , computer science
Milroy disease ( MD ) is an autosomal dominantly inherited primary lymphedema. In 1998, the gene locus for MD was mapped to 5q35.3 and variants in the VEGFR 3 ( FLT 4 ) gene, encoding vascular endothelial growth factor receptor 3 ( VEGFR 3), were identified as being responsible for the majority of MD cases. Several reports have since been published detailing pathogenic FLT 4 mutations. To date, a total of 58 different variants in FLT 4 , 20 of which are unpublished, have been observed in 95 families with MD . A review of published mutations is presented in this update. Furthermore, the unpublished variants are presented including clinical data. Comparison of clinical features in patients and their families with the same mutations reveals incomplete penetrance and variable expression, making genotype–phenotype correlations difficult. Most mutations are missense, but a few deletions and one splicing variant have also been reported. Several animal models have confirmed the role of VEGFR 3 in lymphangiogenesis and studies show mutant VEGFR 3 receptors are not phosphorylated. Here, an MD patient with the same p.Ile1053Phe change as seen in the C hy mouse is presented for the first time. This finding confirms that this mouse lineage is an excellent model for MD . All the data reviewed here has been submitted to a database based on the L eiden O pen (source) V ariation D atabase ( LOVD ) and is accessible online at www.lovd.nl/flt4.