Truncating mutations in FOXC2 cause multiple lymphedema syndromes

• Published in: Human molecular genetics 2001-05, Vol.10 (11), p.1185-1189
• Main Authors: FINEGOLD, David N, KIMAK, Mark A, LAWRENCE, Elizabeth C, LEVINSON, Kara L, CHERNISKE, Elizabeth M, POBER, Barbara R, DUNLAP, Jean W, FERRELL, Robert E
• Format: Article
• Language: English
• Subjects: Adolescent; Adult; Aged; Aged, 80 and over; Base Sequence; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; Child; Chromosomes, Human, Pair 16 - genetics; Cleft Palate - genetics; Diseases of the lymphatic vessels; DNA Mutational Analysis; DNA Primers - chemistry; DNA-Binding Proteins - genetics; Female; Forkhead Transcription Factors; Humans; Infant, Newborn; Lymphedema - genetics; Male; Medical sciences; Middle Aged; Molecular Sequence Data; Mutation - genetics; Polymerase Chain Reaction; Polymorphism, Genetic; Syndrome; Transcription Factors - genetics
• ISSN: 0964-6906; 1460-2083; 1460-2083
• DOI: 10.1093/hmg/10.11.1185

Hereditary lymphedemas are developmental disorders of the lymphatics resulting in edema of the extremities due to altered lymphatic flow. One such disorder, the lymphedema-distichiasis syndrome, has been reported to be caused by mutations in the forkhead transcription factor, FOXC2. We sequenced the FOXC2 gene in 86 lymphedema families to identify mutations. Eleven families were identified with mutations predicted to disrupt the DNA binding domain and/or C-terminal alpha-helices essential for transcription activation by FOXC2. Broad phenotypic heterogeneity was observed within these families. The phenotypes observed overlapped four phenotypically defined lymphedema syndromes. FOXC2 appears to be the primary cause of lymphedema-distichiasis syndrome and is also a cause of lymphedema in families displaying phenotypes attributed to other lymphedema syndromes. Our data demonstrates that the phenotypic classification of autosomal dominant lymphedema does not reflect the underlying genetic causation of these disorders.