LTBP2 and CYP1B1 mutations and associated ocular phenotypes in the Roma/Gypsy founder population

Abstract

Primary congenital glaucoma (PCG) is a genetically heterogeneous autosomal recessive disorder, which is an important cause of blindness in childhood. The first known gene, CYP1B1, accounts for a variable proportion of cases in most populations. A second gene, LTBP2, was recently reported in association with a syndrome, in which glaucoma is secondary to lens dislocation. We report on the molecular and clinical profile of 34 families diagnosed as PCG, all originating from the Roma/ Gypsy founder population. Comprehensive sequencing analysis revealed a level of heterogeneity unusual for this population, with five CYP1B1 and one ancestral LTBP2 mutation accounting for B70% of patients (25 out of 37) and the remainder still unexplained. Homozygosity for the founder LTBP2 p.R299X mutation resulted in a more severe clinical phenotype and poorer outcome despite a markedly higher number of surgical interventions. The genetically homogeneous group of p.R299X homozygotes showed variable phenotypes (presumably also underlying pathogenetic mechanisms), wherein PCG proper with primary dysgenesis of the trabecular meshwork, and Marfan syndrome-like zonular disease with ectopia lentis and later onset secondary glaucoma are two extremes. The spectrum manifestations may occur in different combinations and have a different evolution even within the same sibship or a single patient. Preliminary observations on compounds with mutations in both CYP1B1-LTBP2 suggest that the observed combinations are of no clinical significance and digenic inheritance is unlikely. We provide a population genetics perspective to explain the allelic heterogeneity, comparing the history and geographic distribution of the two major founder mutations -p.R299X/LTBP2 and p.E387K/CYP1B1.

Origins, admixture and founder lineages in European Roma

“…14,17,18 The Indian component of the proto-Roma ancestry was supported by the identification of disease-causing mutations described in affected subjects in India and Pakistan. 9,15,19,20 Furthermore, the Roma show high frequencies of the H-M69 Y-chromosome 4,17,21,22 and mitochondrial DNA (mtDNA) M5, M18, M25, and M35 haplogroups 4,7,17,[23][24][25] reported to have an Indian origin. 25,26,27 Accordingly, studies of autosomal markers identified the Northwest of India as the most probable homeland of the European Roma.…”

Osteopontin and latent-TGF β binding-protein 2 as potential diagnostic markers for HBV-related hepatocellular carcinoma

“…It regulates the assembly of elastic fibers through binding to DANCE/fibulin‐5 and its expression appears to be increased in intrinsically aged skin . In human cancer, LTBP2 has been suggested to act as a suppressor in oesophageal squamous cell carcinoma and is up regulated in human pancreatic ductal adenocarcinoma . In a recent study that used proteomics to characterize cancer‐associated fibroblasts in a mouse model of colorectal carcinogenesis, LTBP2 was identified as one of the components of a desmoplastic signature of four markers that significantly increased in tumor stroma, without significant expression in the cancer epithelial cells .…”

Molecular genetics in glaucoma

“…LTBP2 , latent transforming growth factor beta binding protein 2 (LTBP2) , located in the GLC3C locus, was reported to be associated with PCG by two different studies and confirmed by Azmanov et al (Ali et al, 2009; Azmanov et al, 2010; Narooie-Nejad et al, 2009). Three LTBP2 mutations were reported as either frameshift or nonsense mutations.…”