A novel homozygous missense mutation p.P388S in TULP1 causes protein instability and retinitis pigmentosa

• Published in: Molecular vision 2021, Vol.27, p.179-190
• Main Authors: Woodard, DaNae R, Xing, Chao, Ganne, Pratyusha, Liang, Hanquan, Mahindrakar, Avinash, Sankurathri, Chandrasekhar, Hulleman, John D, Mootha, V Vinod
• Format: Article
• Language: English
• Subjects: Adult; Atrophy; Blindness; Blotting, Western; Children; Confocal microscopy; Consanguinity; Cycloheximide; Electroretinography; Endoplasmic reticulum; Epithelium; Exome Sequencing; Eye Proteins - genetics; Homozygote; Humans; India; Kinases; Male; Microscopy, Confocal; Missense mutation; Mutation; Mutation, Missense - genetics; Nyctalopia; Pedigree; Pigmentation; Proteins; Real-Time Polymerase Chain Reaction; Retina; Retinal degeneration; Retinal pigment epithelium; Retinitis; Retinitis pigmentosa; Retinitis Pigmentosa - diagnosis; Retinitis Pigmentosa - genetics; Retinitis Pigmentosa - physiopathology; Tomography, Optical Coherence; Tubby-like protein 1; Visual Acuity - physiology; Western blotting
• ISSN: 1090-0535; 1090-0535

Retinitis pigmentosa (RP) is an inherited retinal disorder that results in the degeneration of photoreceptor cells, ultimately leading to severe visual impairment. We characterized a consanguineous family from Southern India wherein a 25 year old individual presented with night blindness since childhood. The purpose of this study was to identify the causative mutation for RP in this individual as well as characterize how the mutation may ultimately affect protein function. We performed a complete ophthalmologic examination of the proband followed by exome sequencing. The likely causative mutation was identified and modeled in cultured cells, evaluating its expression, solubility (both with western blotting), subcellular distribution, (confocal microscopy), and testing whether this variant induced endoplasmic reticulum (ER) stress (quantitative PCR [qPCR] and western blotting). The proband presented with generalized and parafoveal retinal pigmented epithelium (RPE) atrophy with bone spicule-like pigmentation in the midperiphery and arteriolar attenuation. Optical coherence tomography scans through the macula of both eyes showed atrophy of the outer retinal layers with loss of the ellipsoid zone, whereas the systemic examination of this individual was normal. The proband's parents and sibling were asymptomatic and had normal funduscopic examinations. We discovered a novel homozygous p.Pro388Ser mutation in the ( ) gene in the individual with RP. In cultured cells, the P388S mutation does not alter the subcellular distribution of TULP1 or induce ER stress when compared to wild-type TULP1, but instead significantly lowers protein stability as indicated with steady-state and cycloheximide-chase experiments. These results add to the list of known mutations in identified in individuals with RP and suggest a possible unique pathogenic mechanism in -induced RP, which may be shared among select mutations in .