TGFB1 and LAMA1 gene polymorphisms in children with high myopia.

OBJECTIVE: To investigate TGFB1 and LAMA1 gene polymorphisms in children with high myopia in order to determine the genetic basis of large myopic shifts causing severe visual impairment and complications. METHODS: Seventy-four children with high myopia (≥6 diopters [D]; study group) and 77 emmetropic children (±0.5D; control group) were included. Genetic and polymorphism analyses were performed in the Medical Genetics Laboratory using DNA purified from the patients' blood samples. RESULTS: Mean ages of the patients were 7.1±3 (3-13) and 9.6±1.8 (6-13) years in the study and control groups, respectively. Mean refraction in the high myopia group were -10.1±4.3D in the right and -8.9±3.6D in the left eye. LAMA1 gene analysis of the study group revealed heterozygous mutations in 34 patients (45.9%), homozygous mutations in 25 patients (33.8%), and no mutations in the remaining 15 patients (20.3%). In the control group, there were 31 subjects (40.3%) with heterozygous, 27 (35.1%) with homozygous LAMA1 mutations, and no mutations in 19 (24.7%) (p=0.73). TGFB1 gene analysis showed heterozygous mutations in 32 (43.2%) and homozygous mutations in 10 patients (13.5%) in the study group, while 32 patients (43.2%) had no mutations. In the control group, 35 subjects (45.5%) had heterozygous, 8 (10.4%) had homozygous, and 34 (44.1%) had no TGFB1 mutations (p=0.36). CONCLUSION: This is the first study to simultaneously examine two genes in high myopia in a Turkish population. However, we observed no significant differences in TGFB1 and LAMA1 gene polymorphisms in patients with high myopia compared to healthy subjects.

Phenotypic spectrum of patients with Poretti-Boltshauser syndrome: Patient report of antenatal ventriculomegaly and esophageal atresia.

Poretti-Boltshauser syndrome (PTBHS) is an autosomal recessive disorder characterized by cerebellar dysplasia with cysts and an abnormal shape of the fourth ventricle on neuroimaging, due to pathogenic variants in the LAMA1 gene. The clinical spectrum mainly consists of neurological and ophthalmological manifestations, including non-progressive cerebellar ataxia, oculomotor apraxia, language impairment, intellectual disability, high myopia, abnormal eye movements and retinal dystrophy. We report a patient presenting with ventriculomegaly on antenatal neuroimaging and a neonatal diagnosis of Type III esophageal atresia. She subsequently developed severe myopia and strabismus with retinal dystrophy, mild developmental delay, and cerebellar dysplasia. Genetic investigations confirmed PTBHS. This report confirms previous reports of antenatal ventriculomegaly in PTBHS patients and documents a so far unreported occurrence of esophageal atresia in PTBHS. We additionally gathered phenotype and genotype descriptions of published cases in an effort to better define the spectrum of PTBHS.

Effect of a Single Nucleotide Polymorphism in the LAMA1 Promoter Region on Transcriptional Activity: Implication for Pathological Myopia.

PURPOSE: To elucidate the role of the protein coding laminin α1 (LAMA1) gene in pathological myopia (PM) at the transcriptional level. To achieve this, the binding affinity of single nucleotide polymorphism (SNP) rs2089760-located on the LAMA1 promoter gene-to human fetal scleral fibroblast (HFSF) nucleoprotein was investigated and its effect on LAMA1 transcriptional initiation activity was analyzed. METHODS: Binding interactions of the HFSF nucleoprotein and biotin-labeled SNP rs2089760 probe were investigated by amplifying the LAMA1 promoter gene and performing overlap extension polymerase chain reaction (PCR) to obtain the G/A mutation of LAMA1 SNP rs2089760. Recombinant adenovirus vectors, Ad5f11p-pLAMA1SNPa-Luc2, Ad5f11p-pLAMA1SNPg-Luc2, and Ad5f11p-CMV-RLuc, were constructed. Fluorescence intensity ratios of firefly luciferase (FLuc) and renilla luciferase (RLuc) vectors were measured 48 h after HFSF infection. RESULTS: Both specific and mutant probes banded precisely with HFSF nucleoprotein. The intensity value of the mutant probe was significantly lower than that of the specific probe (p < 0.05). HFSFs were successfully infected by the recombinant adenoviruses. The FLuc/RLuc fluorescence intensity ratio of Ad5f11p-pLAMA1SNPa-Luc2 (0.0238 ± 0.0009) was significantly lower than that of Ad5f11p-pLAMA1SNPg-Luc2 (0.0281 ± 0.0015) (p < 0.05). CONCLUSIONS: It is highly likely that SNP rs2089760 in the LAMA1 promoter region is located at the transcription factor binding site. The SNP rs2089760 G > A mutation reduces transcription factor binding ability and transcriptional initiation activity, and negatively regulates gene transcription of LAMA1. We suggest that LAMA1 SNP rs2089760 plays an important role in the development of PM.