Novel mutation in the FOXC2 gene in three generations of a family with lymphoedema–distichiasis syndrome

Sutkowska, Edyta; Gil, Justyna; Stembalska, Agnieszka; Hill-Bator, Aneta; Szuba, Andrzej

doi:10.1016/j.gene.2012.01.098

Cited by 19 publications

(9 citation statements)

References 22 publications

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“…To date, approximately 70 FOXC2 mutations have been listed in the HGMD Database, with more than 57 mutations for LD syndrome and 8 for primary lymphedema (www.hgmd.cf.ac.uk). The most common types of FOXC2 gene mutations include missense and nonsense mutations, small deletions and insertions (www.hgmd.cf.ac.uk) 24. Various types of mutations have been found throughout the coding sequence, with approximately 30% in the FHD and approximately 60% in the C-terminal domain, from amino acids 180 to 501.…”

Section: Discussionmentioning

confidence: 99%

Novel FOXC2 Mutation in Hereditary Distichiasis Impairs DNA-Binding Activity and Transcriptional Activation

Zhang

Han

et al. 2016

Int. J. Biol. Sci.

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Distichiasis presents as double rows of eyelashes arising from aberrant differentiation of the meibomian glands of the eyelids, and it may be sporadic or hereditary. FOXC2 gene mutations in hereditary distichiasis are rarely reported. Here, we examined two generations of a Chinese family with hereditary distichiasis but without lymphedema or other features of LD syndrome. The FOXC2 gene was amplified and sequenced in all family members. Subcellular localization and luciferase assays were performed to assess the activity of the mutant FOXC2 protein. Clinical examinations showed distichiasis, lower eyelid ectropion, congenital ptosis and photophobia in all affected individuals. Sequence analysis revealed a novel frameshift mutation, c.964_965insG, in the coding region of the FOXC2 gene. This mutation caused protein truncation due to the presence of a premature stop codon. A fluorescence assay showed that this mutation did not change the nuclear localization of the protein. However, it impaired DNA-binding activity and decreased transcriptional activation. This is the first report of a FOXC2 mutation in hereditary distichiasis in the Chinese population. The findings of our study expand the FOXC2 mutation spectrum and contribute to the understanding of the genotype-phenotype correlation of this disease.

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Section: Discussionmentioning

confidence: 99%

Novel FOXC2 Mutation in Hereditary Distichiasis Impairs DNA-Binding Activity and Transcriptional Activation

Zhang

Han

et al. 2016

Int. J. Biol. Sci.

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“…More recently, our lineage tracing analyses of Foxc2 expressing cardiac neural crest cells revealed that these cells additionally contribute to the aorta, pulmonary trunk, valves, and endocardial cushions (Amin et al, ). Furthermore, studies in mice have indicated that Foxc2 is expressed in, and plays a critical role in proper development of lymphatic vessels and valves (Dagenais et al, ; Petrova et al, ; Seo et al, ; Sabine et al, ), and consistent with these observations, heterozygous mutations in FOXC2 are associated with congenital lymphedema distichiasis in humans (Sutkowska et al, ).…”

Section: Introductionmentioning

confidence: 82%

Foxc2 is required for proper cardiac neural crest cell migration, outflow tract septation, and ventricle expansion

Inman

Caiaffa

Melton

et al. 2018

Developmental Dynamics

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Background: Proper development of the great vessels of the heart, and septation of the cardiac outflow tract requires cardiac neural crest cells. These cells give rise to the parasympathetic cardiac ganglia, the smooth muscle layer of the great vessels, some cardiomyocytes and the conotruncal cushions and aorticopulmonary septum of the outflow tract. Ablation of cardiac neural crest cells results in defective patterning of each of these structures. Previous studies have shown that targeted deletion of the forkhead transcription factor C2 (Foxc2), results in cardiac phenotypes similar to that derived from cardiac neural crest cell ablation. Results: We report that Foxc2−/− embryos on the 129s6/SvEv inbred genetic background display persistent truncus arteriosus and hypoplastic ventricles prior to embryonic lethality. Foxc2 loss-of-function resulted in perturbed cardiac neural crest cell migration and their reduced contribution to the outflow tract as evidenced by lineage tracing analyses together with perturbed expression of the neural crest cell markers Sox10 and Crabp1. Foxc2 loss-of-function also resulted in alterations in PlexinD1, Twist1, PECAM1 and Hand1/2 expression in association with vascular and ventricular defects. Conclusions: Our data indicate Foxc2 is required for proper migration of cardiac neural crest cells, septation of the outflow tract, and development of the ventricles.

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“…There is variable penetrance and expression and variation in age of onset. Lymphoedema of the lower extremities is usually bilateral and asymmetric and is seen in childhood or in adolescence [46]. The lymphedema is observed at an earlier age and presents more problems with cellulitis in males.…”

Section: Lymphedema-distichiasis Syndromementioning

confidence: 99%

“…The syndrome is an autosomal dominant disorder caused by mutations in the FOXC2 gene having varying degrees of penetrance and expression patterns [45]. The most common types of mutations are small deletions, while insertions, duplications, duplicationsinsertion, missense and nonsense mutations are also found [46]. Most of these cause truncation of proteins or loss of protein function (lack of DNA binding capability.…”

Section: Lymphedema-distichiasis Syndromementioning

confidence: 99%

“…The association between FOXC2 gene mutation and primary valve failure in the superficial and deep veins in the lower extremities is very strong [47] as the gene encodes regulatory transcription factor, which plays a role in normal development of the lymphatic and vascular system [48]. Sutkowska et al [46] described a new frame-shift mutation in FOXC2 gene due to deletion of two nucleotides (CC) in C repeats between C586 and C591.47 This leads to a protein truncation due to an earlier appearance of a stop codon.…”

Section: Lymphedema-distichiasis Syndromementioning

confidence: 99%

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Genetics of strabismus and lid diseases

Sadiq

Rehman

2015

J Pediatr Genet

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The prevalence of congenital ocular malformations has been described to vary from 0.04 to 6.8 per 10,000 live births. The nuclear mutations identified in chronic progressive external ophthalmoplegia harbor multiple mtDNA deletions that include POLG mutations, PEO1 mutations, OPA1 mutations and RRM2B mutations. In Kearns-Sayre syndrome, the spontaneous mitochondrial deletions vary from 1.3 to 8.0 kb subunits of the oxidative phosphorylation enzymes and several t-RNA genes are affected. Oculopharyngeal muscle dystrophy is both autosomal dominant and recessive form. Congenital fibrosis of extraocular muscles (CFEOM) 1 has mutations in KIF21A on chromosome 12 with TUBB3 mutation also being seen. CFEOM 2 is an autosomal recessive, genetically distinct entity with homozygous mutations in PHOX2A. CFEOM 3 is autosomal dominant heterozygous missense mutations in TUBB3. Most cases of Mobius syndrome are sporadic with familial cases being autosomal dominant, autosomal recessive or X-linked recessive inheritance. Genetic testing has shown abnormalities involving chromosome 1 and 13. Presynaptic congenital myasthenic syndrome is caused by ChAT (choline acetyltransferase) mutation. Two loci have been found for myotonic dystrophy (DM). DM1, which is associated with trinucleotide expansion on chromosome 19q13.3 and DM2 which is associated with CCTG tetranucleotide expansion at 3q21. Blepharophimosis is caused by mutations in the FOXL2 gene 49 located at chromosome 3q23. Lymphedema-distichiasis is an autosomal dominant disorder caused by mutations in the FOXC2 gene.

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Novel mutation in the FOXC2 gene in three generations of a family with lymphoedema–distichiasis syndrome

Cited by 19 publications

References 22 publications

Novel FOXC2 Mutation in Hereditary Distichiasis Impairs DNA-Binding Activity and Transcriptional Activation

Novel FOXC2 Mutation in Hereditary Distichiasis Impairs DNA-Binding Activity and Transcriptional Activation

Foxc2 is required for proper cardiac neural crest cell migration, outflow tract septation, and ventricle expansion

Genetics of strabismus and lid diseases

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