Biallelic Variants in TULP1 Are Associated with Heterogeneous Phenotypes of Retinal Dystrophy

Abstract

Biallelic pathogenic variants in TULP1 are mostly associated with severe rod-driven inherited retinal degeneration. In this study, we analyzed clinical heterogeneity in 17 patients and characterized the underlying biallelic variants in TULP1. All patients underwent thorough ophthalmological examinations. Minigene assays and structural analyses were performed to assess the consequences of splice variants and missense variants. Three patients were diagnosed with Leber congenital amaurosis, nine with early onset retinitis pigmentosa, two with retinitis pigmentosa with an onset in adulthood, one with cone dystrophy, and two with cone-rod dystrophy. Seventeen different alleles were identified, namely eight missense variants, six nonsense variants, one in-frame deletion variant, and two splice site variants. For the latter two, minigene assays revealed aberrant transcripts containing frameshifts and premature termination codons. Structural analysis and molecular modeling suggested different degrees of structural destabilization for the missense variants. In conclusion, we report the largest cohort of patients with TULP1-associated IRD published to date. Most of the patients exhibited rod-driven disease, yet a fraction of the patients exhibited cone-driven disease. Our data support the hypothesis that TULP1 variants do not fold properly and thus trigger unfolded protein response, resulting in photoreceptor death.

Comprehensive analysis of two hotspot codons in the TUBB4B gene and associated phenotypes

“…This method, which allows the evaluation of the differences in Gibbs free energy of folding (∆∆G f app = ∆G f app mut − ∆G f app WT ) and binding to Tubulin α-1B chain (∆∆G b app = ∆G b app mut − ∆G b app WT ) with respect to the wildtype does not consider the explicit energetic term associated with the conformational change. Therefore, the differences in free energy reported in this study cannot be considered precise thermodynamic values, but they represent variations in apparent stability (∆∆G f app ) or affinity (∆∆G b app ), which nevertheless have been proven to correlate with functional data also in other protein systems 35 .…”

Deciphering complexity: TULP1 variants linked to an atypical retinal dystrophy phenotype

“…In both scenarios, the introduction of a premature stop codon is likely to activate the NMD mechanism, ultimately resulting in the absence of protein production from this allele ( Figure 4B ). Similarly, Bodenbender et al (2023) performed minigene assays for the c.1495+1G>A and c.1496–6C>A TULP1 variants. In both cases, the variants were predicted to induce frameshift variants and premature termination codons, leading to the probable degradation of the mutant transcript via the NMD mechanism.…”

“… Bodenbender et al (2023) reported a total of 17 different TULP1 pathogenic variants, categorized as missense, splice site, and nonsense variants, and one in-frame deletion. All documented variants, except the missense variant p.(Gly266Val), either affected the tubby domain or led to LOF ( Figure 5 ).…”

“…The link between TULP1 and autosomal recessive IRDs was first established in 1998 ( Banerjee et al, 1998 ; Hagstrom et al, 1998 ). Since then, TULP1 biallelic variants have been extensively associated with various forms of IRDs, including non-syndromic RP, Leber congenital amaurosis, cone dystrophy, and rod–cone dystrophy ( Ullah et al, 2016 ; Bodenbender et al, 2023 ). To date, the LOVD database ( www.lovd.nl/gene , accessed on 13 January 2024) records a total of 117 unique TULP1 variants.…”

“… Bodenbender et al (2023) reported the largest TULP1 -related IRD cohort to date. This research established a connection between biallelic TULP1 variants and a wide range of clinical phenotypes, emphasizing the remarkable heterogeneity in TULP1 -related retinal dystrophy.…”