Alternative titles; symbols
HGNC Approved Gene Symbol: FOXC2
SNOMEDCT: 8634009;
Cytogenetic location: 16q24.1 Genomic coordinates (GRCh38): 16:86,566,829-86,569,728 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 16q24.1 | Lymphedema-distichiasis syndrome | 153400 | Autosomal dominant | 3 |
| Lymphedema-distichiasis syndrome with renal disease and diabetes mellitus | 153400 | Autosomal dominant | 3 |
The 'forkhead' (or winged helix) gene family, originally identified in Drosophila, encodes transcription factors with a conserved 100-amino acid DNA-binding motif. Using RT-PCR of brain mRNA, Miura et al. (1993) isolated a mouse gene containing a forkhead domain, which they designated Mfh1 for 'mesenchyme forkhead-1.' They found that Mfh1 is expressed temporally in mouse embryos, first in nonnotochordal mesoderm and later in developing mesenchyme.
Miura et al. (1997) used the mouse gene to clone human MFH1 (FOXC2), which encodes a predicted 501-amino acid protein with 94% sequence identity to mouse MFH1. Both human and mouse MFH1 are intronless and act as transactivators of transcription in transfected cells.
Cederberg et al. (2001) identified FOXC2 as a key regulator of adipocyte metabolism. In mice overexpressing Foxc2 in white adipose tissue (WAT) and brown adipose tissue (BAT), the intraabdominal WAT depot was reduced and had acquired a brown fat-like histology, whereas interscapular BAT was hypertrophic. Increased Foxc2 expression had a pleiotropic effect on gene expression in BAT and WAT. There was an induction of the BAT-specific gene Ucp1 (113730) in the intraabdominal WAT depot. The authors also demonstrated a change in steady-state levels of several WAT- and BAT-derived mRNAs that encode genes of importance for adipocyte insulin action, differentiation, metabolism, sensitivity to adrenergic stimuli, and intracellular signaling. The nature of these Foxc2-generated responses was consistent with protection against obesity and related symptoms, such as diet-induced insulin resistance. Furthermore, in wildtype mice, Foxc2 mRNA levels were upregulated by high-fat diet, whereas mice with targeted disruption of 1 Foxc2 allele had a decreased interscapular BAT cell mass. Cederberg et al. (2001) concluded that FOXC2 affects adipocyte metabolism by increasing the sensitivity of the beta-adrenergic cAMP protein kinase A (PKA; see 176911) signaling pathway through alteration of adipocyte PKA holoenzyme composition. Furthermore, they stated that increased FOXC2 levels induced by high fat diet seem to counteract most of the symptoms associated with obesity, including hypertriglyceridemia and diet-induced insulin resistance, and a likely consequence would be protection against type II diabetes.
Using gene expression profiling, Mani et al. (2007) found that FOXC2, a gene involved in specifying mesenchymal cell fate during embryogenesis, was associated with metastatic capabilities of cancer cells. Foxc2 expression was required for murine mammary carcinoma cells to metastasize to lung, and overexpression of Foxc2 enhanced their metastatic potential. FOXC2 was induced in human and mouse cells undergoing epithelial-mesenchymal transitions (EMTs) triggered by a number of signals. FOXC2 specifically promoted mesenchymal differentiation during an EMT, suggesting that FOXC2 orchestrates the mesenchymal component of the EMT program. FOXC2 was significantly overexpressed in the highly aggressive basal-like subtype of human invasive ductal breast cancer.
Mellor et al. (2007) examined 18 FOXC2 mutation-positive individuals from 7 families with lymphedema-distichiasis syndrome (LPHDST; 153400) previously reported by Bell et al. (2001) and Brice et al. (2002), and detected reflux in the great saphenous vein in all 18 and deep venous reflux in 14, including in 3 mutation carriers who did not have lymphedema. Only 1 of 12 controls examined, 10 of whom were mutation-negative family members, had superficial or deep venous reflux. Mellor et al. (2007) stated that FOXC2 was the first gene in which mutations were strongly associated with primary venous valve failure in both the superficial and deep veins in the lower limb, and concluded that the gene is important for the normal development and maintenance of venous and lymphatic valves.
Kaestner et al. (1996) mapped the respective MFH1 genes to mouse chromosome 8 by linkage analysis and to human chromosome 16q22-q24 by fluorescence in situ hybridization. In mouse, Mfh1 is 8 kb from another forkhead family member, designated Fkh6 (FOXL1; 603252); the 2 genes are similarly arranged in humans.
Fang et al. (2000) determined that the FOXC2 gene contains a single coding exon and spans approximately 1.5 kb.
The lymphedema-distichiasis syndrome (LPHDST; 153400) is an autosomal dominant disorder that presents with lymphedema of the limbs, with variable age at onset, and double rows of eyelashes. The complications may include cardiac defects, cleft palate, extradural cysts, and photophobia, suggesting a defect in a gene with pleiotropic effects acting during development. Mangion et al. (1999) mapped the disorder to chromosome 16q24.3. In affected members of 2 families with lymphedema-distichiasis syndrome, Fang et al. (2000) identified 2 inactivating mutations (602402.0001 and 602402.0002) in the FOXC2 gene.
Bell et al. (2001) reported the mutation analysis of 14 families with lymphedema-distichiasis syndrome. All but 1 of these pedigrees had small insertions or deletions in the FOXC2 gene, which seemed likely to produce haploinsufficiency. The mutation sites were scattered throughout the gene. The exceptional family had a missense mutation (602402.0012) in the forkhead domain of the protein.
Finegold et al. (2001) identified mutations in FOXC2 in 11 of 86 families with lymphedema-distichiasis syndrome; mutations were 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 authors observed overlapping phenotypically defined lymphedema syndromes: Meige lymphedema (153200), lymphedema-distichiasis syndrome, and yellow nail syndrome (153300), but not Milroy disease (153100). The authors stated that the phenotypic classification of autosomal dominant lymphedema does not appear to reflect the underlying genetic causation of these disorders.
Rezaie et al. (2008) disputed the clinical diagnoses of some of the patients reported by Finegold et al. (2001). In particular, 10 of the 11 families reported by Finegold et al. (2001) had distichiasis, consistent with the lymphedema-distichiasis syndrome. The last family was not reported to have either yellow nails or distichiasis, but Rezaie et al. (2008) emphasized that the detection of distichiasis is often difficult to confirm and cannot be assumed to be absent from patient self-reports. In addition, Rezaie et al. (2008) did not identify mutations in the FOXC2 gene in 22 unrelated probands with Meige disease, i.e., lymphedema without distichiasis. One additional proband was found to carry a FOXC2 mutation, but detailed ophthalmologic examination revealed accessory eyelashes in him and his affected family members, thus confirming the diagnosis of lymphedema-distichiasis.
Yildirim-Toruner et al. (2004) reported a family of German-Irish descent with lymphedema-distichiasis syndrome in 6 members over 3 generations. In addition to LPHDST, 4 had renal disease and 3 had type II diabetes. All affected members were found to have a frameshift mutation in the FOXC2 gene (1006insA; 602402.0010); all affected and unaffected members of the family were homozygous for the T allele of the 512C-T polymorphism in the 5-prime UTR of the FOXC2 gene. This polymorphism had been found to be associated with insulin sensitivity in Swedish persons (Ridderstrale et al., 2002) but not in Japanese (Osawa et al., 2003) or Pima Indians (Kovacs et al., 2003). Yildirim-Toruner et al. (2004) suggested that the phenotype of LPHDST, renal disease, and diabetes might be the result of a combination of the mutation and the polymorphism.
Sholto-Douglas-Vernon et al. (2005) reported the ascertainment of 34 families and 11 sporadic cases of lymphedema-distichiasis syndrome in the United Kingdom. In 2 families linked to the FOXC2 locus, no mutations or deletions were identified, leaving promoter mutations as the most likely cause of disease. Sixteen previously unpublished mutations were reported, including 2 missense mutations.
Van Steensel et al. (2009) screened a cohort of 288 patients with primary noncongenital lymphedema for mutations in the FLT4 (136352), SOX18 (601618), and FOXC2 genes, and identified 4 mutations in FLT4 and 11 in FOXC2. Five of the FOXC2 changes were predicted to truncate the protein, and 6 were missense mutations. Two of the missense mutations were located within the forkhead DNA-binding domain, including the previously reported S125L mutation (602402.0012) and an R121C substitution (602402.0014), whereas the remaining 4 occurred outside the forkhead domain (see, e.g., 602402.0015 and 602402.0016). Functional analysis in HeLa Ohio and COS-7 cells showed that all 4 FOXC2 missense mutations outside the forkhead domain increased transcriptional and transactivation activity, whereas the missense mutations within the forkhead domain showed reduced activity. No genotype/phenotype correlations were observed. The authors concluded that gain-of-function mutations in FOXC2 can also cause lymphedema.
Michelini et al. (2012) screened the FLT4 and FOXC2 genes in a cohort of 46 Italian probands with primary lymphedema and identified FLT4 mutations in 6 (13%) and FOXC2 mutations in 6 (13%; see, e.g., 602402.0017). Tavian et al. (2016) restudied the 6 Italian probands with FOXC2-associated lymphedema. Consistent with previous reports, the 3 patients with activating mutations showed lymphatic hypoplasia on scintigraphy, whereas the 3 patients with inactivating mutations showed hyperplasia, suggesting a genotype/phenotype correlation. The authors stated that the association between FOXC2 function and distichiasis was less clear: all 3 patients with activating mutations had distichiasis, whereas it was present in only 1 of the 3 patients with inactivating mutations. Tavian et al. (2016) concluded that either complete loss or significant gain of FOXC2 function can cause a perturbation of lymphatic vesesel formation resulting in lymphedema.
Associations Pending Confirmation
In 900 dizygotic female twin pairs who had responded to a self-administered questionnaire regarding varicose veins (192200), Ng et al. (2005) found significant linkage between D16S520, located about 80 kb from FOXC2, and varicose veins, but found no association. Ng et al. (2005) suggested that FOXC2 is implicated in the development of varicose veins in the general population.
In 10 patients with alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV; 265380) associated with multiple congenital anomalies, Stankiewicz et al. (2009) identified 6 overlapping microdeletions encompassing the FOX transcription factor gene cluster, all but 1 of which included the FOXF1 gene; they also identified heterozygosity for point mutations in 4 unrelated ACDMPV patients (601089.0001-601089.0004, respectively). Stankiewicz et al. (2009) noted that in contrast to the association of point mutations in FOXF1 with bowel malrotation, microdeletions of FOXF1 were associated with hypoplastic left heart syndrome and gastrointestinal atresias, which they suggested was due to haploinsufficiency for the neighboring FOXC2 and FOXL1 (603252) genes.
Smith et al. (2000) reported that Mfh1 +/- mice have anterior segment abnormalities similar to those reported in humans with Axenfeld-Rieger anomaly: small or absent canal of Schlemm, aberrantly developed trabecular meshwork, iris hypoplasia, severely eccentric pupils, and displaced Schwalbe line, but with normal intraocular pressure. The penetrance of clinically obvious abnormalities varied with genetic background. In some affected eyes, collagen bundles were half normal diameter, or collagen and elastic tissue were very sparse, suggesting that abnormalities in extracellular matrix synthesis or organization may contribute to development of the ocular phenotypes. No disease-associated mutations were identified in the human homolog FKHL14 in 32 Axenfeld-Rieger anomaly patients. Similar abnormalities were found in Foxc1 +/- (FOXC1; 601090) mice.
Kume et al. (2001) found that Foxc1 -/- Foxc2 -/- compound homozygous mice died earlier with much more severe defects than single homozygotes alone. Compound homozygous mice had profound abnormalities in the first and second branchial arches and in early remodeling of blood vessels. They showed complete absence of segmented paraxial mesoderm, including anterior somites. In situ hybridization showed that both Foxc1 and Foxc2 were required for transcription in the anterior presomitic mesoderm of paraxis (TCF15; 601010), Mesp1 (608689), Mesp2 (605195), Hes5 (607348), and Notch1 (190198) and for formation of sharp boundaries of Dll1 (606582), Lfng (602576), and ephrin B2 (EFNB2; 600527) expression. Kume et al. (2001) proposed that FOXC1 and FOXC2 interact with the Notch signaling pathway and are required for prepatterning of anterior and posterior domains in the presumptive somites through a putative Notch/Delta/Mesp regulatory loop.
Kriederman et al. (2003) performed dynamic lymphatic imaging and immunohistochemical examination of lymphatic tissues in mice heterozygous for a targeted disruption of Foxc2. Adult heterozygous mice characteristically exhibited a generalized lymphatic vessel and lymph node hyperplasia and rarely exhibited hindlimb swelling. Retrograde lymph flow through apparently incompetent interlymphangion valves into the mesenteric nodes, intestinal wall, and liver was also observed. In addition, Foxc2 heterozygous mice uniformly displayed distichiasis. Kriederman et al. (2003) noted that the craniofacial, cardiovascular, and skeletal abnormalities sometimes associated with lymphedema-distichiasis syndrome had previously been shown to be fully penetrant in homozygous Foxc2-null mice (Iida et al., 1997; Winnier et al., 1997). They concluded that Foxc2 haploinsufficient mice mimic closely the distinctive lymphatic and ocular phenotype of patients with lymphedema-distichiasis syndrome.
In a family with lymphedema-distichiasis syndrome (LPHDST; 153400), Fang et al. (2000) found that affected members had a 297C-G transversion, in the FOXC2 gene, resulting in a tyr99-to-ter (Y99X) substitution. The first member of this family studied was a fetus that, because of hydrops fetalis, was electively aborted at 17 weeks' gestation. The fetal karyotype was 46,XX. The father was diagnosed with hereditary lymphedema-distichiasis, and 2 sons had distichiasis. An earlier pregnancy was electively aborted because of the presence of hydrops and presumed Turner syndrome, although subsequent pathologic examination did not show internal abnormalities compatible with Turner syndrome. The family history suggested that the hydrops fetalis seen in the 2 fetuses was a result of the lymphedema-distichiasis gene mutation.
In affected members of a family with lymphedema-distichiasis syndrome (LPHDST; 153400), Fang et al. (2000) found a 4-nucleotide (GGCC) duplication at position 1093 of the coding region of the FOXC2 gene. The mutation, which would create 98 novel amino acids before truncating the protein, lay in the carboxy-terminal region after the forkhead domain. In addition to lymphedema and distichiasis, affected members of the family had cystic hygroma, arachnoid cysts, and cleft palate.
In a family in which multiple members had lymphedema-distichiasis syndrome (LPHDST; 153400), Bell et al. (2001) found an 11-bp deletion involving nucleotides 290-300 and resulting in the creation of 361 novel amino acids beginning at codon 96.
In a family in which members in 3 successive generations had lymphedema-distichiasis syndrome (LPHDST; 153400), Bell et al. (2001) found deletion of 1331A, disrupting codon 443, producing a frameshift, and adding 27 novel amino acids.
In a family with cases of lymphedema-distichiasis syndrome (LPHDST; 153400) in 3 successive generations, Bell et al. (2001) found insertion of a T after nucleotide 209, causing disruption of codon 70 and a frameshift with addition of 391 novel amino acids.
In a sporadic case of lymphedema-distichiasis syndrome (LPHDST; 153400), Bell et al. (2001) found a dinucleotide insertion of CT after nucleotide 201, disrupting codon 67 and causing a frameshift with production of 4 novel amino acids.
In a family with lymphedema-distichiasis syndrome (LPHDST; 153400), Finegold et al. (2001) identified a 1-bp insertion (5890insC) in the FOXC2 gene, resulting in a frameshift with premature termination at amino acid 463. Age of onset of lymphedema was after puberty. One patient had distichiasis, and another had a cleft palate.
Finegold et al. (2001) identified the same mutation in affected members of another family with LPHDST. Three of 7 affected family members also exhibited ptosis, and 3 also had yellow nails, thus suggesting phenotypic overlap between lymphedema-distichiasis syndrome and lymphedema-yellow nail syndrome (153300).
Rezaie et al. (2008) disputed some of the diagnoses of Finegold et al. (2001), and noted that yellow discoloration of the nails is not uncommon with lymphedema, but does not necessarily indicate a diagnosis of so-called 'yellow nail syndrome,' in which the nail changes are very specific. In yellow nail syndrome, the nail plate is yellow and over-curved but it remains translucent and smooth. By contrast, in lymphedema not associated with yellow nail syndrome, the nails become thickened, rough and opaque. Associated features such as chronic sinusitis, bronchiectasis or pleural effusion are often essential for a diagnosis of yellow nail syndrome. Indeed, Finegold et al. (2001) found no FOXC2 mutations in 4 families with lymphedema and yellow nail syndrome. Rezaie et al. (2008) concluded that the families with the 589insC mutation were most consistent with lymphedema-distichiasis syndrome.
In a family with lymphedema-distichiasis syndrome (LPHDST; 153400), Finegold et al. (2001) found a 1-bp deletion (505delA) in the FOXC2 gene, resulting in a frameshift with premature termination at amino acid 202. Age of onset of lymphedema ranged from 8 to 13 years among affected family members. Two individuals had ptosis, and 1 had tetralogy of Fallot.
Bahuau et al. (2002) reported a family showing autosomal dominant segregation of upper- and lower-eyelid distichiasis in 7 relatives over 3 generations, in addition to below-knee lymphedema of pubertal onset in 3 (LPHDST; 153400). Two children had cleft palate in addition to distichiasis, but without the previously reported association of Pierre Robin sequence (Bell et al., 2001; Brice et al., 2002). Other ophthalmologic anomalies included divergent strabismus and early-onset myopia. Although no family member had pterygium colli, congenital heart disease, or facial dysmorphism, the disorder was linked to markers on chromosome 16q24.3 and was thus proposed to be allelic to lymphedema-distichiasis syndrome. Bahuau et al. (2002) demonstrated an out-of-frame deletion of the FOXC2 gene, 914-921del, segregating with the syndrome. Whether the heterogeneity observed was related to genotype-phenotype correlation, a hypothesis not primarily supported by the apparent loss-of-function mechanism of the mutations, or governed by modifying genes, was undetermined.
In 6 affected members spanning 3 generations of a German-Irish family with lymphedema-distichiasis syndrome (see 153400), Yildirim-Toruner et al. (2004) identified a 1-bp insertion (1006insA) in the FOXC2 gene, resulting in a frameshift mutation that predicted a premature stop at codon 462. In addition to lymphedema-distichiasis syndrome, 4 of the affected members had renal disease and 3 had type II diabetes mellitus (see 125853), features not usually seen in LPHDST. Sequence analysis of the 5-prime untranslated region for the 512C-T polymorphism showed the homozygous T allele in all family members tested. The earliest affected member of the family was 73 years old at the time of report and was on chronic renal dialysis. One of her sons, aged 45 years, had developed proteinuria at age 32 years. Renal biopsy showed chronic sclerosing glomerulopathy and chronic tubulointerstitial nephritis. One member of the family underwent renal transplantation and, shortly thereafter, pancreatic transplantation, both with excellent results. She was 36 years old at the time of report and had distichiasis but no lymphedema. Yildirim-Toruner et al. (2004) concluded that the novel phenotype of LPHDST with renal disease and type II diabetes might be the result of a combination of the 1-bp coding region insertion and homozygosity for the T allele of the upstream UTR 512C-T polymorphism.
In affected members of a family with lymphedema-distichiasis syndrome (LPHDST; 153400), originally reported by Falls and Kertesz (1964), Erickson et al. (2001) identified a heterozygous 5-bp insertion (602insACAAA) followed by a 79-bp deletion in the FOXC2 gene, resulting in a frameshift and premature termination of the protein at codon 436.
In affected members of a family with lymphedema-distichiasis syndrome (LPHDST; 153400), previously reported by Mangion et al. (1999), Bell et al. (2001) identified a 374C-T transition in the FOXC2 gene, resulting in a ser125-to-leu (S125L) substitution at a conserved residue. The mutation was not identified in 100 normal chromosomes.
Berry et al. (2005) analyzed the molecular consequences of the S125L mutation in the DNA-recognition helix of the forkhead domain (FHD) of FOXC2. A mutation model based on the paralogous FOXC1 (601090) protein predicted that S125L would impair DNA binding and transcriptional activation ability of the FOXC2 protein, and biochemical analysis confirmed the prediction. Berry et al. (2005) concluded that the S125L mutation is a functional null and that FOXC2 haploinsufficiency underlies hereditary LPHDST.
From a cohort of 288 patients with primary noncongenital lymphedema, van Steensel et al. (2009) identified 1 patient who was heterozygous for the S125L mutation in the FOXC2 gene. The patient had erysipelas from age 10 years as well as lymphedema, varicose veins, and superficial and deep venous insufficiency. Family history was positive for lymphedema, but family members were not available for study. Although distichiasis was not reported in this patient, the authors noted that it is a feature that can be quite subtle and might have been missed. Functional analysis in HeLa Ohio and COS-7 cells showed reduced transcriptional and transactivation activity with the S125L mutant compared to wildtype FOXC2.
In a sporadic case of lymphedema-distichiasis syndrome (LPHDST; 153400), Brice et al. (2002) identified a 362G-A transition in the FOXC2 gene, resulting in an arg121-to-his (R121H) substitution at a conserved residue. The mutation was not identified in 100 normal chromosomes.
Berry et al. (2005) analyzed the molecular consequences of the R121H mutation in the DNA-recognition helix of the forkhead domain (FHD) of FOXC2. A mutation model based on the paralogous FOXC1 (601090) protein predicted that R121H would impair DNA binding and transcriptional activation ability of the FOXC2 protein, and biochemical analysis confirmed the prediction. Also, the R121H mutation affected the nuclear localization of FOXC2. Berry et al. (2005) concluded that the R121H mutation is a functional null and that FOXC2 haploinsufficiency underlies hereditary LPHDST.
From a cohort of 288 patients with primary noncongenital lymphedema, van Steensel et al. (2009) identified 1 patient with lymphedema-distichiasis syndrome (LPHDST; 153400) who was heterozygous for a c.361C-T transition (GenBank NG_012025.1) in the FOXC2 gene, resulting in an arg121-to-cys (R121C) substitution at a highly conserved residue within the forkhead domain. The mutation was not found in 100 Dutch controls or in the dbSNP (build 130) database. The patient had swelling of feet and neck at birth, developed lymphedema, and also had superficial and deep venous insufficiency. Although distichiasis was not reported, the authors noted that it is a feature that can be quite subtle and might have been missed. Functional analysis in HeLa Ohio and COS-7 cells showed reduced transcriptional and transactivation activity with the R121C mutant compared to wildtype FOXC2.
From a cohort of 288 patients with primary noncongenital lymphedema, van Steensel et al. (2009) identified 1 patient with lymphedema-distichiasis syndrome (LPHDST; 153400) who was heterozygous for a c.122A-T transversion (GenBank NG_012025.1) in the FOXC2 gene, resulting in a tyr41-to-phe (Y41F) substitution at a highly conserved residue. The mutation was not found in 100 Dutch controls or in the dbSNP (build 130) database. The patient had swollen feet at birth and developed varicose veins. Family history was positive for lymphedema, but family members were not available for study. Although distichiasis was not reported in this patient, the authors noted that it is a feature that can be quite subtle and might have been missed. Functional analysis in HeLa Ohio and COS-7 cells showed increased transcriptional and transactivation activity with the Y41F mutant compared to wildtype FOXC2.
From a cohort of 288 patients with primary noncongenital lymphedema, van Steensel et al. (2009) identified 1 patient with lymphedema-distichiasis syndrome (LPHDST; 153400) who was heterozygous for a c.1205C-T transition (GenBank NG_012025.1) in the FOXC2 gene, resulting in a pro402-to-leu (P402L) substitution at a highly conserved residue. The mutation was not found in 100 Dutch controls or in the dbSNP (build 130) database. The patient developed lymphedema at age 16 years, followed by varicose veins and insufficiency of the deep venous system with thrombosis in the right lower extremity. Scintigraphy showed minimal uptake (0.5% on the right and 1.7% on the left, with clearance of 94% and 92%, respectively), consistent with lymphatic hypoplasia. Family history was positive for lymphedema, but family members were not available for study. Although distichiasis was not reported in this patient, the authors noted that it is a feature that can be quite subtle and might have been missed. Functional analysis in HeLa Ohio and COS-7 cells showed increased transcriptional and transactivation activity with the P402F mutant compared to wildtype FOXC2.
In a 28-year-old Italian man and his son with lymphedema-distichiasis (LPHDST; 153400), Michelini et al. (2012) identified heterozygosity for a c.1258C-T transition in the FOXC2 gene, resulting in a gln420-to-ter (Q420X) substitution. Although Michelini et al. (2012) stated that distichiasis was not present in this family, Tavian et al. (2016) restudied the father (patient 4) and detected distichiasis by slit-lamp examination.
Tavian et al. (2016) performed functional analysis of the Q420X mutant in HeLa and COS-7 cells and observed a significant increase (257%) in transcriptional activity compared to wildtype protein. Patient scintigraphy was consistent with lymphatic hypoplasia. The father also had bicuspid aortic valve.
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