LTBP2 null mutations in an autosomal recessive ocular syndrome with megalocornea, spherophakia, and secondary glaucoma

Abstract

The latent TGFβ-binding proteins (LTBPs) and fibrillins are a superfamily of large, multidomain proteins with structural and TGFβ-signalling roles in the extracellular matrix. Their importance is underscored by fibrillin-1 mutations responsible for Marfan syndrome, but their respective roles are still incompletely understood. We report here on two families where children from healthy, consanguineous parents, presented with megalocornea and impaired vision associated with small, round, dislocated lenses (microspherophakia and ectopia lentis) and myopia, as well as a high-arched palate, and, in older children, tall stature with an abnormally large arm span over body height ratio, that is, associated features of Marfan syndrome. Glaucoma was not present at birth, but was diagnosed in older children. Whole genome homozygosity mapping followed by candidate gene analysis identified homozygous truncating mutations of LTBP2 gene in patients from both families. Fibroblast mRNA analysis was consistent with nonsense-mediated mRNA decay, with no evidence of mutated exon skipping. We conclude that biallelic null LTBP2 mutations cause the ocular phenotype in both families and could lead to Marfan-like features in older children. We suggest that intraocular pressures should be followed-up in young children with an ocular phenotype consisting of megalocornea, spherophakia and/or lens dislocation, and recommend LTBP2 gene analysis in these patients.

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

“…In patient 32-3 the phenotype was similar to that described by Désir et al, 15 except for the earlier onset of glaucoma. The child was referred to the clinic at age 5 months because of buphthalmos and iridodonesis, and diagnosed with bilateral lens dislocation.…”

“…However, p.R299X homozygotes had undergone more surgical interventions (3.1 vs 0.8 per affected eye) and the outcome in visual acuity was poorer: 11 out of 26 eyes with no light perception as compared with 3 out of 22 among CYP1B1 mutants. At the same time, the PCG diagnosis in p.R299X homozygotes was established at a significantly later age (15.1 months vs 3.6 months in the CYP1B1 group), which could be because of a later onset, similar to the patients described by Désir et al 15 One of the Désir et al 15 cases was a Gypsy child, p.R299X homozygous, with normal IOP at age 3 years.…”

“…47 So far, both ocular manifestations and the presence/absence of other MFS-like features in LTBP2 defects appear variable and combinatorial. 13,15,16 We are currently unable to comment on the presence of extra-ocular manifestations: most p.R299X homozygotes in the study have been clinically examined before the identification of the LTBP2 gene with no record of abnormalities found upon physical examination, whereas recently ascertained cases are young children, in whom the diagnosis of MFS-like features is still uncertain. The question whether lens dislocation in p.R229X homozygotes tends to occur in combination with other MFS-like features merits further study, as it may be related to the underlying mechanisms -whether random and unpredictable, or involving sequence variation in the fibrillin 1 gene in addition to the truncating LTBP2 mutation(s).…”

“…12 Analysis of the candidate gene LTBP2, encoding latent transforming growth factor-b-binding protein 2, identified truncating mutations in PCG patients from Pakistan and Iran. 13,14 Recently, homozygous mutations in LTBP2 were reported in a syndrome of megalocornea, microspherophakia (small spherical lens), lens dislocation, and secondary glaucoma developing after age 3 years 15 and in isolated microspherophakia/lens dislocation. 16 In the original studies, 13,14 ectopia lentis was rare, found in some (but not all) affected members in single families.…”

The clinical spectrum of complete FBN1 allele deletions

“…This is in keeping with the observation that mutations in LTBP2 (latent-transforming growth factor-b-binding protein 2) cause recessive eye abnormalities including ectopia lentis. 39,40 LTBP2 is the only member of the LTBP family not to bind to latent forms of TGFb, and is thought to have an important structural role in the ciliary body together with fibrillin-1. 41 In conclusion, our patients with a complete FBN1 allele deletion show that haploinsufficiency has a major contribution to the pathogenesis of MFS and can lead tot the whole spectrum of MFS.…”