Mutations in ASPH Cause Facial Dysmorphism, Lens Dislocation, Anterior-Segment Abnormalities, and Spontaneous Filtering Blebs, or Traboulsi Syndrome

Abstract

We have previously described a syndrome characterized by facial dysmorphism, lens dislocation, anterior-segment abnormalities, and spontaneous filtering blebs (FDLAB, or Traboulsi syndrome). In view of the consanguineous nature of the affected families and the likely autosomal-recessive inheritance pattern of this syndrome, we undertook autozygosity mapping and whole-exome sequencing to identify ASPH as the disease locus, in which we identified two homozygous mutations. ASPH encodes aspartyl/asparaginyl β-hydroxylase (ASPH), which has been found to hydroxylate aspartic acid and asparagine residues on epidermal growth factor (EGF)-domain-containing proteins. The truncating and missense mutations we identified are predicted to severely impair the enzymatic function of ASPH, which suggests a possible link to other forms of ectopia lentis given that many of the genes implicated in this phenotype encode proteins that harbor EGF domains. Developmental analysis of Asph revealed an expression pattern consistent with the proposed link to the human syndrome. Indeed, Asph-knockout mice had a foreshortened snout, which corresponds to the facial abnormalities in individuals with Traboulsi syndrome. These data support a genetic basis for a syndromic form of ectopia lentis and the role of aspartyl hydroxylation in human development.

Mapping and Exploring the Collagen-I Proteostasis Network

“…Asp hydroxylation in collagen-I has likely been previously overlooked because traditional MS protocols for analysis of collagen begin with proteolytic removal of the propeptides. Intriguingly, ASPH mutations were very recently identified as causative factors in facial dysmorphism, 34 supporting a possible role in the maturation of extracellular matrix proteins like collagen-I and motivating further mechanistic work in this area.…”

Recessive Mutations inLEPREL1Underlie a Recognizable Lens Subluxation Phenotype

“…17 The rare recessive syndrome of ectopia lentis, spontaneous filtering blebs and craniofacial dysmorphism, is due to recessive ASPH mutations and thus far only been documented in the Middle East. [18][19][20][21] Children with sulfite oxidase deficiency (isolated, from recessive mutations in SUOX, or non-isolated, in the context of other deficiencies) have major neurological abnormalities early in life; while lens subluxation is often present, it is typically not a presenting feature. 22 Usually these different genetic causes of ectopia lentis are phenotypically distinct; however, rarely there can be phenotypic overlap when genes that interact with each other in the extracellular matrix are mutated.…”

Systems biology of lens development: A paradigm for disease gene discovery in the eye

“…Thus, such analysis benefits from additional biological insights through iSyTE . Indeed, several studies have successfully applied iSyTE in their investigations of eye and lens defects in human patients, namely for: 1) prioritization of novel candidate genes for pediatric cataract (Aldahmesh et al, 2012); 2) prioritization of promising candidates for anophthalmia and microphthalmia (Schilter et al, 2013); 3) linking ADAMTS18 in ocular syndrome in microcornea and myopia (Aldahmesh et al, 2013), 4) linking STX3 to congenital cataract (Chograni et al, 2014), and 5) identifying ASPH mutations that are associated with Traboulsi syndrome with ocular lens dislocation (Patel et al, 2014). Further, in 2012 iSyTE correctly predicted SIPA1l3 as a cataract-linked gene (Fig.…”