title: Maternal uniparental isodisomy of chromosome 6 reveals a TULP1 mutation as a novel cause of cone dysfunction.
abstract: OBJECTIVE
  The majority of the genetic causes of autosomal recessive (ar) cone dystrophy (CD) and cone-rod dystrophy (CRD) are currently unknown. We used a high-resolution homozygosity mapping approach in a cohort of patients with CD or CRD to identify new genes for ar cone disorders.
  
  
  METHODS
  Case series.
  
  
  METHODS
  A cohort of 159 patients with ar CD and 91 patients with CRD.
  
  
  METHODS
  The genomes of 83 patients with ar CD and 73 patients with CRD were analyzed for homozygous regions using single nucleotide polymorphism (SNP) microarrays. One patient showed homozygosity of SNPs across chromosome 6, and segregation analysis was performed using microsatellite markers. Direct sequencing of all retinal disease genes on chromosome 6 revealed a novel pathogenic TULP1 mutation in this patient. A cohort of 159 individuals with CD and 91 individuals with CRD was screened for this particular mutation using the restriction enzyme HhaI. The medical history of patients carrying the TULP1 mutation was reviewed and additional ophthalmic examinations were performed, including electroretinography (ERG), perimetry, optical coherence tomography (OCT), fundus autofluorescence (FAF), and fundus photography.
  
  
  METHODS
  TULP1 mutations, age at diagnosis, visual acuity, fundus appearance, color vision defects, visual field, ERG, FAF, and OCT findings.
  
  
  RESULTS
  In 1 patient, homozygosity mapping and subsequent segregation analysis revealed maternal uniparental disomy (UPD) of chromosome 6. A novel homozygous missense mutation (p.Arg420Ser) was identified in TULP1, whereas no mutations were detected in other retinal disease genes on chromosome 6. The mutation affects a highly conserved amino acid residue in the Tubby domain and is predicted to be pathogenic. The same homozygous mutation was also identified in an additional, unrelated patient with CRD. Both patients carrying the p.Arg420Ser mutation presented with a bull's eye maculopathy. The first patient had progressive loss of visual acuity with a relatively preserved ERG, whereas the second patient developed loss of visual acuity, peripheral degeneration, and severely reduced ERG responses in a cone-rod pattern.
  
  
  CONCLUSIONS
  Maternal UPD of chromosome 6 unmasked a mutation in the TULP1 gene as a novel cause of cone dysfunction. This expands the disease spectrum of TULP1 mutations from Leber congenital amaurosis and early-onset retinitis pigmentosa to cone-dominated disease.
  
  
  BACKGROUND
  The author(s) have no proprietary or commercial interest in any materials discussed in this article.
authors.affiliation: Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
authors.forename: Susanne
authors.initials: S
authors.lastname: Roosing
authors.forename: L Ingeborgh
authors.initials: LI
authors.lastname: van den Born
authors.forename: Carel B
authors.initials: CB
authors.lastname: Hoyng
authors.forename: Alberta A H J
authors.initials: AA
authors.lastname: Thiadens
authors.forename: Elfride
authors.initials: E
authors.lastname: de Baere
authors.forename: Rob W J
authors.initials: RW
authors.lastname: Collin
authors.forename: Robert K
authors.initials: RK
authors.lastname: Koenekoop
authors.forename: Bart P
authors.initials: BP
authors.lastname: Leroy
authors.forename: Norka
authors.initials: N
authors.lastname: van Moll-Ramirez
authors.forename: Hanka
authors.initials: H
authors.lastname: Venselaar
authors.forename: Frans C C
authors.initials: FC
authors.lastname: Riemslag
authors.forename: Frans P M
authors.initials: FP
authors.lastname: Cremers
authors.forename: Caroline C W
authors.initials: CC
authors.lastname: Klaver
authors.forename: Anneke I
authors.initials: AI
authors.lastname: den Hollander
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D002896:Chromosomes, Human, Pair 6 / Q000235:genetics*; D003117:Color Vision Defects / Q000235:genetics*; D004596:Electroretinography; D005136:Eye Proteins / Q000235:genetics*; D005260:Female; D005451:Fluorescein Angiography; D006720:Homozygote; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D008969:Molecular Sequence Data; D009035:Mothers; D020125:Mutation, Missense; D010375:Pedigree; D020419:Photoreceptor Cells, Vertebrate / Q000473:pathology; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D017433:Protein Structure, Secondary; D017949:Retinal Cone Photoreceptor Cells / Q000473:pathology*; D058499:Retinal Dystrophies / Q000235:genetics*; D041623:Tomography, Optical Coherence; D024182:Uniparental Disomy / Q000235:genetics*; D014792:Visual Acuity / Q000502:physiology; D058609:Visual Field Tests
chemical_list: D005136:Eye Proteins; C105443:TULP1 protein, human