Novel L558P Mutation of the TGFBI Gene Found in Ukrainian Families with Atypical Corneal Dystrophy

Abstract

Purpose: To report a novel L558P mutation of the human transforming growth factor β-induced (TGFBI) gene found in Ukrainian families with atypical corneal dystrophy (CD). Methods: Genomic DNA was extracted from peripheral leukocytes of 12 members of 4 unrelated families with atypical CD. We performed genotype analysis of these families with microsatellite markers surrounding the TGFBI locus. Exons of the TGFBI gene were amplified by polymerase chain reaction (PCR), and directly sequenced in 5 patients of 4 unrelated families. We utilized a simple PCR/restriction fragment length polymorphism-based technique for L558P mutation identification. Fifty normal individuals were also analyzed as controls. These assays were complemented by histological analysis of available corneal buttons excised during penetrating keratoplasty. Results: A heterozygous single-base-pair transition (CTC to CCC, leucine to proline) at codon 558 in exon 12 of the TGFBI gene (L558P) was detected in 10 individuals. Eight are affected, and 2 are teenagers with no clinical manifestation of the disease as yet. The mutation was not found in 2 healthy individuals from 2 high-risk CD families, nor in 50 normal controls. Histopathological examination identified amyloid deposits, mostly in the posterior central cornea. Haplotype analysis provided evidence of a common founder of the L558P mutation. The mutation works on the protein level by disrupting an α-helix, which is crucial for the normal functioning of keratoepithelin. Conclusion: A novel L558P mutation in the TGFBI gene causes an atypical type of stromal CD.

Transforming growth factor beta‐induced p.(L558P) variant is associated with autosomal dominant lattice corneal dystrophy type IV in a large cohort of Spanish patients

“…The pathogenicity of p.(L558P) variant was initially supported by its autosomal dominant co‐inheritance with the atypical CD in our cohort of Spanish families. Similar findings have been reported in four Ukrainian families and a different Spanish family . Moreover, the absence of reported frequency values in different genomic databases such as ExAC and Ensembl, the high evolutionary conservation of the mutated amino acid and the predicted damaging effect on protein function, further support the deleterious effect of this variant.…”

“…According with previous reports, we found that the p.(L558P) variant is associated with an atypical LCD characterized by bilateral punctuated opacities and branched filamentous deposits . Also, p.(L558P) carriers showed a late CD onset with the first manifestations observed at variable ages ranging from the third to the fifth decade of life.…”

“…Herein we report the clinical characterization of, to the best of our knowledge, the largest CD cohort carrying the TGFBI p.(L558P) variant, which can be considered representative of the South European population. This sequence variant has previously been found only in patients from two apparently unrelated Ukrainian families and in three cases from a unique Spanish family . Therefore, the high prevalence of this variant among the studied Spanish families may indicate the existence of a founder effect, although a detailed analysis of genetic markers is required to confirm this hypothesis.…”

“…The characteristic phenotype associated with p.(L558P) has been ambiguously classified as “atypical LCD” in previous reports . According to the IC3D classification of CD, a previously documented CD with not yet convincing evidence of being a distinct entity is classified as category 4 .…”

A Migration Signature and Plasma Biomarker Panel for Pancreatic Adenocarcinoma

“…In addition, 3 of the 7 genes, L1CAM , TGFBI , and CDC42BPA , identified as most differentially expressed, are mutated in the germline in genetic disorders including CRASH syndrome, Thiel–Behnke corneal dystrophy, and Crohn’s disease, respectively (58, 59). Given that germline mutations underlying genetic disorders are very rare, the finding that our study identified 3 of 7 genes as being mutated in hereditary diseases indicates the functional significance of this migration pathway in early development, the deregulation of which could be of critical importance in pancreatic cancer initiation and progression.…”