7 results found
Dudakova L, Tuft S, Cheong S, et al., 2021, Novel disease‐causing variants and phenotypic features of X‐linked megalocornea, Acta Ophthalmologica, ISSN: 1755-375X
PurposeThe aim of the study was to describe the phenotype and molecular genetic causes of X-linked megalocornea (MGC1). We recruited four British, one New Zealand, one Vietnamese and four Czech families.MethodsAll probands and three female carriers underwent ocular examination and Sanger sequencing of the CHRDL1 gene. Two of the probands also had magnetic resonance imaging (MRI) of the brain.ResultsWe identified nine pathogenic or likely pathogenic and one variant of uncertain significance in CHRDL1, of which eight are novel. Three probands had ocular findings that have not previously been associated with MGC1, namely pigmentary glaucoma, unilateral posterior corneal vesicles, unilateral keratoconus and unilateral Fuchs heterochromic iridocyclitis. The corneal diameters of the three heterozygous carriers were normal, but two had abnormally thin corneas, and one of these was also diagnosed with unilateral keratoconus. Brain MRI identified arachnoid cysts in both probands, one also had a neuroepithelial cyst, while the second had a midsagittal neurodevelopmental abnormality (cavum septum pellucidum et vergae).ConclusionThe study expands the spectrum of pathogenic variants and the ocular and brain abnormalities that have been identified in individuals with MGC1. Reduced corneal thickness may represent a mild phenotypic feature in some heterozygous female carriers of CHRDL1 pathogenic variants.
Cheong SS, Akram K, Metellan C, et al., 2020, The planar polarity component Vangl2 is a key regulator of mechanosignaling, Frontiers in Cell and Developmental Biology, Vol: 8, ISSN: 2296-634X
VANGL2 is a component of the planar cell polarity (PCP) pathway, which regulates tissue polarity and patterning. The Vangl2Lp mutation causes lung branching defects due to dysfunctional actomyosin-driven morphogenesis. Since the actomyosin network regulates cell mechanics, we speculated that mechanosignaling could be impaired when VANGL2 is disrupted. Here, we used live-imaging of precision-cut lung slices (PCLS) from Vangl2Lp/+ mice to determine that alveologenesis is attenuated as a result of impaired epithelial cell migration. Vangl2Lp/+ tracheal epithelial cells (TECs) and alveolar epithelial cells (AECs) exhibited highly disrupted actomyosin networks and focal adhesions (FAs). Functional assessment of cellular forces confirmed impaired traction force generation in Vangl2Lp/+ TECs. YAP signaling in Vangl2Lp airway epithelium was reduced, consistent with a role for VANGL2 in mechanotransduction. Furthermore, activation of RhoA signaling restored actomyosin organization in Vangl2Lp/+, confirming RhoA as an effector of VANGL2. This study identifies a pivotal role for VANGL2 in mechanosignaling, which underlies the key role of the PCP pathway in tissue morphogenesis.
Dean C, Cheong SS, 2019, On the move: the commander IL-4 leads the cell army in collective migration, American Journal of Respiratory Cell and Molecular Biology, Vol: 60, Pages: 377-378, ISSN: 1044-1549
Dudakova L, Cheong S-S, Merjava SR, et al., 2018, Familial Limbal Stem Cell Deficiency: Clinical, Cytological and Genetic Characterization, STEM CELL REVIEWS AND REPORTS, Vol: 14, Pages: 148-151, ISSN: 1550-8943
Cheong S-S, Hull S, Jones B, et al., 2017, Pleiotropic effect of a novel mutation in GCNT2 causing congenital cataract and a rare adult i blood group phenotype, Human Genome Variation, Vol: 4, ISSN: 2054-345X
Mutations in GCNT2 have been associated with the rare adult i blood group phenotype with or without congenital cataract. Wereport a novel homozygous frameshift mutation c.1163_1166delATCA, p.(Asn388Argfs*20) as the cause of congenital cataract intwo affected siblings. Blood group typing confirmed that both affected males have the rare adult i phenotype, supporting thehypothesis that the partial association of I/i phenotype and congenital cataract is due to the differential expression of GCNT2isoforms.
Cheong S-S, Hentschel L, Davidson AE, et al., 2016, Mutations in CPAMD8 cause a unique form of autosomal-recessive anterior segment dysgenesis, American Journal of Human Genetics, Vol: 99, Pages: 1338-1352, ISSN: 0002-9297
Anterior segment dysgeneses (ASDs) comprise a spectrum of developmental disorders affecting the anterior segment of the eye. Here, we describe three unrelated families affected by a previously unclassified form of ASD. Shared ocular manifestations include bilateral iris hypoplasia, ectopia lentis, corectopia, ectropion uveae, and cataracts. Whole-exome sequencing and targeted Sanger sequencing identified mutations in CPAMD8 (C3 and PZP-like alpha-2-macroglobulin domain-containing protein 8) as the cause of recessive ASD in all three families. A homozygous missense mutation in the evolutionarily conserved alpha-2-macroglobulin (A2M) domain of CPAMD8, c.4351T>C (p. Ser1451Pro), was identified in family 1. In family 2, compound heterozygous frameshift, c.2352_2353insC (p.Arg785Glnfs∗23), and splice-site, c.4549-1G>A, mutations were identified. Two affected siblings in the third family were compound heterozygous for splice-site mutations c.700+1G>T and c.4002+1G>A. CPAMD8 splice-site mutations caused aberrant pre-mRNA splicing in vivo or in vitro. Intriguingly, our phylogenetic analysis revealed rodent lineage-specific CPAMD8 deletion, precluding a developmental expression study in mice. We therefore investigated the spatiotemporal expression of CPAMD8 in the developing human eye. RT-PCR and in situ hybridization revealed CPAMD8 expression in the lens, iris, cornea, and retina early in development, including strong expression in the distal tips of the retinal neuroepithelium that form the iris and ciliary body, thus correlating CPAMD8 expression with the affected tissues. Our study delineates a unique form of recessive ASD and defines a role for CPAMD8, a protein of unknown function, in anterior segment development, implying another pathway for the pathogenicity of ASD.
Davidson AE, Cheong S-S, Hysi PG, et al., 2014, Association of CHRDL1 mutations and variants with X-linked megalocornea, Neuhauser syndrome and central corneal thickness, PLoS ONE, Vol: 9, ISSN: 1932-6203
We describe novel CHRDL1 mutations in ten families with X-linked megalocornea (MGC1). Our mutation-positive cohort enabled us to establish ultrasonography as a reliable clinical diagnostic tool to distinguish between MGC1 and primary congenital glaucoma (PCG). Megalocornea is also a feature of Neuhäuser or megalocornea-mental retardation (MMR) syndrome, a rare condition of unknown etiology. In a male patient diagnosed with MMR, we performed targeted and whole exome sequencing (WES) and identified a novel missense mutation in CHRDL1 that accounts for his MGC1 phenotype but not his non-ocular features. This finding suggests that MMR syndrome, in some cases, may be di- or multigenic. MGC1 patients have reduced central corneal thickness (CCT); however no X-linked loci have been associated with CCT, possibly because the majority of genome-wide association studies (GWAS) overlook the X-chromosome. We therefore explored whether variants on the X-chromosome are associated with CCT. We found rs149956316, in intron 6 of CHRDL1, to be the most significantly associated single nucleotide polymorphism (SNP) (p = 6.81×10−6) on the X-chromosome. However, this association was not replicated in a smaller subset of whole genome sequenced samples. This study highlights the importance of including X-chromosome SNP data in GWAS to identify potential loci associated with quantitative traits or disease risk.
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