Abstract
Posterior amorphous corneal dystrophy (PACD) is a rare, autosomal dominant disorder affecting the cornea and iris. Next-generation sequencing of the previously identified PACD linkage interval on chromosome 12q21.33 failed to yield a pathogenic mutation. However, array-based copy number analysis and qPCR were used to detect a hemizygous deletion in the PACD linkage interval containing 4 genes encoding small leucine-rich proteoglycans (SLRPs): KERA, LUM, DCN, and EPYC. Two other unrelated families with PACD also demonstrated deletion of these SLRPs, which play important roles in collagen fibrillogenesis and matrix assembly. Given that these genes are essential to the maintenance of corneal clarity and the observation that knockout murine models display corneal phenotypic similarities to PACD, we provide convincing evidence that PACD is associated with haploinsufficiency of these SLRPs.
Highlights
Posterior amorphous corneal dystrophy (PACD [MIM 612868]) is a rare, autosomal dominant disorder in which affected individuals typically demonstrate partial or complete posterior lamellar corneal opacification, decreased corneal thickness, and flattening of the corneal curvature
Keratocan (KERA [MIM 603288]), lumican (LUM [MIM 600616]), decorin (DCN [MIM 125255]), and epiphycan (EPYC, known as DSPG3 [MIM 601657]), encode small leucine-rich proteoglycans (SLRPs), a family of proteins involved in collagen fibrillogenesis and matrix assembly
Mutations in the SLRPs have been associated with abnormalities of corneal clarity and curvature, with missense and nonsense mutations in KERA implicated in autosomal recessive cornea plana (CNA2 [MIM 217300]) [13,14,15,16,17,18,19,20], and nonsense mutations in DCN involved in congenital hereditary stromal dystrophy (CSCD [MIM 610048]) [21,22,23]
Summary
Posterior amorphous corneal dystrophy (PACD [MIM 612868]) is a rare, autosomal dominant disorder in which affected individuals typically demonstrate partial or complete posterior lamellar corneal opacification, decreased corneal thickness, and flattening of the corneal curvature. Genome-wide linkage analysis performed on the largest PACD family identified to date demonstrated linkage to a 3.5 Mb region on chromosome 12q21.33, to which 26 genes have been mapped (Annotation Release 104) [1] Four of these genes, keratocan (KERA [MIM 603288]), lumican (LUM [MIM 600616]), decorin (DCN [MIM 125255]), and epiphycan (EPYC, known as DSPG3 [MIM 601657]), encode small leucine-rich proteoglycans (SLRPs), a family of proteins involved in collagen fibrillogenesis and matrix assembly. Keratocan (KERA [MIM 603288]), lumican (LUM [MIM 600616]), decorin (DCN [MIM 125255]), and epiphycan (EPYC, known as DSPG3 [MIM 601657]), encode small leucine-rich proteoglycans (SLRPs), a family of proteins involved in collagen fibrillogenesis and matrix assembly In the cornea, these SLRPs are bound to glycosaminoglycans, forming the ground substance of the cornea, and play an essential role in the maintenance of corneal transparency [11,12]. After large scale sequencing of the PACD interval failed to reveal a pathogenic coding region mutation, we performed copy number analysis in this and two other affected families and discovered that PACD is associated with a deletion of KERA, LUM, DCN, and EPYC
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
