title: A TULP1 founder mutation, p.Gln301*, underlies a recognisable congenital rod-cone dystrophy phenotype on the Arabian Peninsula.
abstract: BACKGROUND
  In Arabian children referred with retinal dystrophy, we have observed that a specific biallelic nonsense mutation in the gene encoding tubby-like protein 1 (TULP1, c.901C>T (p.Gln301*)) is recurrent. This makes the mutation and its associated childhood retinopathy particularly interesting for genetic diagnostic and, potentially, gene therapy approaches. We characterise the ophthalmic phenotype associated with recessive p.Gln301* mutation in TULP1 and assess the mutation for single founder effect.
  
  
  METHODS
  Retrospective consecutive case series (2011-2014) of 10 Arabian children (8 families) homozygous for the p.Gln301* mutation (detected after next-generation sequencing) and 12 ethnically matched controls. TULP1 haplotypes were constructed by analysis of TULP1 intragenic single nucleotide polymorphisms from next-generation sequencing data and genotyping of gene-flanking polymorphic microsatellite markers.
  
  
  RESULTS
  All 10 children (2-8 years old; mean 5.2, median 6) had nystagmus since soon after birth, a grossly normal posterior pole other than arteriolar attenuation, peripheral mottling with apparent evolution to bone spicules, and hyperopia. Rod function was non-recordable while cone function was present (albeit depressed and delayed); however, repeat electroretinogram years later in two children revealed loss of recordable cone function. Autofluorescence showed a hyper-fluorescent ring around the fovea while central optical coherence tomography was within normal limits. A specific haplotype was associated with p.Gln301* and was not present in controls.
  
  
  CONCLUSIONS
  The TULP1 allele p.Gln301* represents a founder mutation on the Arabian Peninsula and is associated with a recognisable congenital recessive rod-cone dystrophy phenotype in the homozygous state.
authors.affiliation: Division of Pediatric Ophthalmology, King Khaled Eye Specialist Hospital, Riyadh, Saudi Arabia.
authors.forename: Arif O
authors.initials: AO
authors.lastname: Khan
authors.affiliation: Bioscientia Center for Human Genetics, Ingelheim, Germany.
authors.forename: Carsten
authors.initials: C
authors.lastname: Bergmann
authors.affiliation: Bioscientia Center for Human Genetics, Ingelheim, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Eisenberger
authors.affiliation: Bioscientia Center for Human Genetics, Ingelheim, Germany Renal Division, Department of Medicine, University Medical Center Freiburg, Freiburg, Germany Institute of Human Genetics, University Hospital of Cologne, Cologne, Germany.
authors.forename: Hanno J
authors.initials: HJ
authors.lastname: Bolz
mesh_terms: D000483:Alleles; D002648:Child; D002675:Child, Preschool; D018389:Codon, Nonsense; D004596:Electroretinography; D005136:Eye Proteins / Q000235:genetics*; D005260:Female; D018703:Founder Effect; D006720:Homozygote; D006801:Humans; D008297:Male; D009759:Nystagmus, Pathologic / Q000235:genetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012174:Retinitis Pigmentosa / Q000151:congenital / Q000235:genetics*; D012189:Retrospective Studies; D012529:Saudi Arabia; D041623:Tomography, Optical Coherence; D014792:Visual Acuity / Q000502:physiology
chemical_list: D018389:Codon, Nonsense; D005136:Eye Proteins; C105443:TULP1 protein, human
keywords: Child health (paediatrics); Dystrophy; Electrophysiology; Retina