Duplication events downstream of IRX1 cause North Carolina macular dystrophy at the MCDR3 locus

Sci Rep. 2017 Aug 8;7(1):7512. doi: 10.1038/s41598-017-06387-6.


Autosomal dominant North Carolina macular dystrophy (NCMD) is believed to represent a failure of macular development. The disorder has been linked to two loci, MCDR1 (chromosome 6q16) and MCDR3 (chromosome 5p15-p13). Recently, non-coding variants upstream of PRDM13 (MCDR1) and a duplication including IRX1 (MCDR3) have been identified. However, the underlying disease-causing mechanism remains uncertain. Through a combination of sequencing studies on eighteen NCMD families, we report two novel overlapping duplications at the MCDR3 locus, in a gene desert downstream of IRX1 and upstream of ADAMTS16. One duplication of 43 kb was identified in nine families (with evidence for a shared ancestral haplotype), and another one of 45 kb was found in a single family. Three families carry the previously reported V2 variant (MCDR1), while five remain unsolved. The MCDR3 locus is thus refined to a shared region of 39 kb that contains DNAse hypersensitive sites active at a restricted time window during retinal development. Publicly available data confirmed expression of IRX1 and ADAMTS16 in human fetal retina, with IRX1 preferentially expressed in fetal macula. These findings represent a major advance in our understanding of the molecular genetics of NCMD and provide insights into the genetic pathways involved in human macular development.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADAMTS Proteins / genetics*
  • ADAMTS Proteins / metabolism
  • Adult
  • Base Sequence
  • Chromosome Duplication
  • Chromosomes, Human, Pair 5 / chemistry
  • Chromosomes, Human, Pair 6 / chemistry
  • Corneal Dystrophies, Hereditary / diagnostic imaging
  • Corneal Dystrophies, Hereditary / genetics*
  • Corneal Dystrophies, Hereditary / pathology
  • Eye Proteins / genetics*
  • Eye Proteins / metabolism
  • Family
  • Female
  • Fetus
  • Gene Expression
  • Genetic Loci*
  • Haplotypes
  • Homeodomain Proteins / genetics*
  • Homeodomain Proteins / metabolism
  • Humans
  • Male
  • Retina / metabolism
  • Retina / pathology
  • Sequence Analysis, DNA
  • Tomography, Optical Coherence
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism


  • Eye Proteins
  • Homeodomain Proteins
  • IRX1 protein, human
  • Transcription Factors
  • ADAMTS Proteins
  • ADAMTS16 protein, human

Supplementary concepts

  • Macular dystrophy, retinal, 1, North Carolina type