Human Molecular Genetics, 2001, Vol. 10, No. 11 1185-1189
© 2001 Oxford University Press
Truncating mutations in FOXC2 cause multiple lymphedema syndromes
1Department of Human Genetics, Graduate School of Public Health and 2Department of Pediatrics, School of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA and 3Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA
Received 14 February 2001; Revised and Accepted 16 March 2001.
DDBJ/EMBL/GenBank accession no. NM_005251.
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONRESULTSDISCUSSIONSUBJECTS AND METHODSREFERENCES |
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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
-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. |
INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONSUBJECTS AND METHODSREFERENCES |
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Hereditary lymphedema is a chronic disabling condition which results in swelling of the extremities due to altered lymphatic flow. Patients with lymphedema suffer from recurrent local infections, physical impairment and social anxiety, and may be at increased risk for developing cancers such as lymphangiosarcoma. Hereditary lymphedema may occur as an isolated condition, examples of which include Milroy disease (OMIM 153100) and lymphedema praecox (OMIM 153200), or as a component of a complex syndrome. We have demonstrated that mutations in the kinase domain of the vascular endothelial growth factor receptor-3 (VEGFR3) gene causes Milroy disease (1), and this finding has been confirmed (2). Syndromic lymphedema-cholestasis (OMIM 214900) has been mapped to a 6 cM region on chromosome 15 (3). The syndrome of lymphedema-distichiasis (OMIM 153400) was mapped to a narrow region of chromosome 16 (4), containing the FOXC2(MFH-1) gene, and mutations in FOXC2 have been identified in families with lymphedema-distichiasis (5). We sequenced the FOXC2 gene in a series of 86 families ascertained through an individual identified with lymphedema to determine the extent of allelic heterogeneity in the FOXC2 gene, and subsequently examined the extent of phenotypic heterogeneity in families with FOXC2 mutations.
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RESULTS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONSUBJECTS AND METHODSREFERENCES |
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Mutations in the coding region of the FOXC2 gene were identified in 11 families of mixed European ancestry ascertained through a proband with lymphedema. Detailed results of the mutation screening are given in Table 1. Each mutation was found to segregate with lymphedema risk in the family in which it was observed, although DNA samples were not available for every family member on whom phenotypic information was available. One mutation, a single nucleotide insertion, was observed in two independently ascertained families (families D and E). The exact nucleotide position of this insertion cannot be specified as it occurs in a contiguous sequence of five cytosines. Genotyping of a series of flanking microsatellite markers (D16S2624, D16S511 and D16S402) over a 19 cM region and a FOXC2 single nucleotide polymorphism (SNP) located between D16S2624 and D16S511 suggest that the mutation in these two families arose independently, as they do not share flanking marker haplotypes. The coding region of FOXC2 was sequenced in 75 randomly ascertained, unrelated individuals of mixed European ancestry, and none of the variations described in Table 1 were observed. The absence of the mutations noted in Table 1 in unaffected individuals, cosegregation of these mutations with lymphedema risk in families, and the fact that the mutations seen in the patients with lymphedema are predicted to lead to protein truncation, support the causative nature of these mutations. Mutations included a 7 bp (family I) and a 14 bp (family A) duplication-insertion, four single base insertions (families D, E, F and J), two single base deletions (families C and H), deletions of 16 bp (family K) and 19 bp (family G), and a C
T transition (family B). The net effect of these mutations was predicted to create a premature termination of the mature protein. The forkhead domain of FOXC2 is reported to extend from nucleotides 211 to 510 (GenBank accession no. NM_005251). Three of the mutations occurred within the forkhead domain and would be likely to disrupt DNA binding. The remaining eight mutations occurred following the forkhead domain and lead to truncations of the mature protein and elimination of key -helical domains required for the interaction of FOXC2 with the transcription complex (6).
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Among the subgroup of 71 families and 75 controls, all of mixed European ancestry, three polymorphisms were identified (Table 2). One SNP was identified in the promoter region and two others were identified in the coding region. The allele frequencies are noted in Table 2.
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The age, sex, lymphedema affection status and age at onset are given in Table 3. The individuals in whom sequencing identified mutations are noted. Ten of the 11 lymphedema families contained at least one individual with distichiasis. In family B, the only observed phenotype was lymphedema. There was no obvious correlation between the site of the mutation or the predicted protein alteration and the phenotypes observed within a family.
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Onset of lymphedema in affected members of these families was between birth and 30 years of age. The average age of onset was 13.7 years and the median onset was 13 years. Of the 44 individuals with lymphedema, three had an unknown age of onset and 29 had a peripubertal onset (lymphedema praecox). Four individuals (ages 6–12 years) with distichiasis but not lymphedema have not reached the median age at onset for lymphedema and may still develop lymphedema. As observed in families with congenital lymphedema due to VEGFR3 mutations, not all mutation carriers express lymphedema. One FOXC2 mutation carrier, a 41-year-old female (family A), failed to show any clinical phenotype. A 22-year-old female (family G), for whom DNA was not available, was reported to have ptosis as the only clinical finding. Other features observed in these families included distichiasis, cleft palate, ptosis, yellow nails, congenital heart defects and cystic hygroma.
Among the 86 families screened, distichiasis was reported in three families in which we did not detect a mutation in the FOXC2 coding sequence. Sequencing of 1168 bp of the 5'-flanking region of FOXC2 in these families did not reveal further mutations. The phenotypic features of distichiasis families without FOXC2 mutations were indistinguishable from those families with FOXC2 mutations (data not shown). The families without FOXC2 mutations were too small to exclude linkage to the chromosome 16q24 region and the possibility of undetected FOXC2 mutations cannot be excluded. Four families with lymphedema-yellow nails syndrome did not demonstrate a FOXC2 mutation.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONSUBJECTS AND METHODSREFERENCES |
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We report the occurrence of mutations in the FOXC2 gene in families with the lymphedema-distichiasis syndrome, as well as in a family with lymphedema and without distichiasis. The mutations reported and the truncated proteins predicted to result from these mutations appear causal for the phenotypes seen and confirm FOXC2 as a causal gene for developmental abnormalities in the lymphatic system. The finding of mutations in a lymphedema family without distichiasis highlights the phenotypic variability associated with FOXC2 mutations.
The phenotypic classification of dominantly inherited lymphedema includes Milroy disease (OMIM 153100), Meige lymphedema (lymphedema praecox) (OMIM 153200), lymphedema-distichiasis syndrome (OMIM 153400), lymphedema and ptosis (OMIM 15300) and yellow-nail syndrome (OMIM 153300). The age at onset data from Table 2 and data from the two families described by Fang et al. (5) suggest that FOXC2 mutations are not etiologic of Milroy disease, which is associated with early childhood onset (pre-pubertal) lymphedema. However, the phenotypes observed in our 11 families overlap the findings reported in Meige syndrome, lymphedema-distichiasis syndrome, lymphedema-ptosis syndrome and yellow nail syndrome. Hence, the phenotypic classification of autosomal dominant lymphedema does not reflect the underlying genetic causation of these disorders.
The mutations identified in families with and without distichiasis occur within or shortly after the critically conserved forkhead domain, where they are expected to interfere with DNA binding or to disrupt C-terminal -helices critical for transcription activation by the forkhead transcription factor. The forkhead/hepatic nuclear factor motif is found in a family of transcription factors with unique DNA binding characteristics, first described by Weigel et al. (7). The forkhead domain is characterized by a highly conserved 110 amino acid sequence, the structure of which consists of -helices and ß-strands separated by two wing-like domains. Since the three-dimensional structure can be visualized in the shape of a butterfly, the region has been referred to as a ‘winged helix’ (8). Fourteen contact points define the interaction with DNA resulting in high specificity of binding. Footprint and deletion studies confirm the necessity to maintain this motif as a structural unit (9–11). While the flanking regions of the forkhead domain have not been as extensively studied as the forkhead region itself, regions in both the C- and N-terminus are known to be essential for transcriptional activation (6). Mutations in members of this diverse gene family have been shown to cause a variety of disease phenotypes (5,12–19). No distinct phenotypic features distinguished our families with mutations directly within the forkhead domain from those where the mutation was observed 3' following the forkhead region. The majority of mutations identified would be predicted to generate a normal core forkhead domain followed by a variable length nonsense peptide. We agree with the conclusion reached by Fang et al. (5) that FOXC2 mutations may exert their actions through a mechanism of haploinsufficiency. However, the possibility exists that the C-terminal missense peptide which results from downstream truncations following insertion and deletion mutations may exert a dominant gain of function effect in some families. The identification of FOXC2 gene mutations in our pedigrees which are characterized by multiple features of varied lymphedema syndromes supports the hypothesis that classification of lymphedema syndromes by phenotypic features is inconsistent with the genetic variations determined through mutational analysis.
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SUBJECTS AND METHODS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONSUBJECTS AND METHODSREFERENCES |
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Subjects
All families were ascertained based on the presence of primary lymphedema in at least two family members. Families were ascertained through the Lymphedema Family Study website (www.pitt.edu/~genetics/lymph) through local referral, and two families were referred through GeneTests, an online genetic testing resource (www.genetests.org), by Yale University School of Medicine and Stanford University. Of the 86 families screened, 71 were of mixed European ancestry. These 71 families included the families identified with mutations (11) and polymorphisms (3). The remaining 15 families were of mixed ethnicity. This study was reviewed and approved by the Institutional Review Board of the University of Pittsburgh and written informed consent was obtained for each individual who participated. Medical records were requested to confirm medical diagnoses of lymphedema and associated phenotypes.
Mutation detection
Sequencing of FOXC2 was performed on 86 probands ascertained with lymphedema, who were found to be negative for mutations in VEGFR3 by direct sequencing. A subset of this group also reported evidence of distichiasis and/or other features of the lymphedema-distichiasis syndrome. Amplification and sequencing primers were designed from the FOXC2 cDNA (GenBank accession no. NM_005251) and from Fang et al. (5). Exonic sequences were amplified in two overlapping segments using the following primer combinations: 1F, 5'-TCTCTCGCGCTCTCTCGCTC-3' and 1R2, 5'-CGTTCGCAGGGTCATGATGTT-3' (62°ta, 1.5 mM Mg++, 6% final concentration DMSO); and 1F2, 5'-GTCATCACCAAGGTGGAGACG-3' with 1R, 5'-CTTTTTTGCGTCTCTGCAGCCC-3' (60°ta, 1.0 mM Mg++, 6% final concentration DMSO). These primers amplify a sequence beginning 90 bp 5' to the reported FOXC2 ATG start site and ending 95 bp 3' from the end of the coding sequence. This provided an overlap of 170 bp in the middle of the single exon. The same primers and conditions were used to sequence 75 unrelated, healthy control subjects of mixed European ancestry.
Primers to amplify additional 5' sequence containing potential control elements were designed from a bacterial artificial chromosome clone (GenBank accession no. AC009108.8) containing FOXC2. This clone, which also contained homologs FOXL1 and FOXF1, was acquired using the DoubleTwist biologic search service. Promoter region PCR was performed using the following combinations: PF1, 5'-CAGTCAGCACGTTGCTAC-3' with PR1, 5'-CTTCTTGCTGAAAGCGAG-3' and PF2, 5'-GATTGGCTCAAAGTTCCG-3' (55°ta, 2.0 mM Mg++, 8% final concentration DMSO) with PR2, 5'-GCATGCTGCTTCCGAGAC-3' (55°ta, 1.25 mM Mg++, 8% final concentration DMSO). These primer sets amplify 1168 bp of 5'-flanking sequence with an overlap of 66 bp in the middle of this region.
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ACKNOWLEDGEMENTS |
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We thank the family members who participated in this study. We thank Peter Chase, M.D. for examining key family members. We acknowledge the sequencing performed by the University of Pittsburgh Center for Genomic Sciences Sequencing Core Facility. This work was supported by NIH Grant R01 HD37243.
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FOOTNOTES |
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+ To whom correspondence should be addressed. Tel: +1 412 624 3018; Fax: +1 412 624 3020; Email: dnf@mars.upmc.edu
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REFERENCES |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONSUBJECTS AND METHODSREFERENCES |
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