TULP1 – Retinitis Pigmentosa

Mutations in the TULP1 gene underlie an autosomal recessive form of Retinitis pigmentosa characterized by early-onset night blindness and progressive photoreceptor loss. The RP14 locus was mapped to chromosome 6p21.3, and TULP1 was implicated based on its retinal expression and the rapid degeneration observed in mouse Tub mutations. Subsequent genetic studies have confirmed TULP1 as a critical gene in rod-cone dystrophy.

A splice-site variant, c.1495+1G>A, was found homozygous in 33 affected individuals and heterozygous in 50 obligate carriers from two extended Dominican kindreds, demonstrating complete cosegregation in an autosomal recessive pattern ([PMID:9462751]). This early mapping study established TULP1 deficiency as a rare but definitive cause of arRP.

A distinct case report described a single proband with maternal uniparental isodisomy of chromosome 6 unmasking a novel homozygous frameshift variant, c.524dupC (p.Pro176ThrfsTer7), recapitulating a rod-cone dystrophy phenotype including congenital nystagmus and nyctalopia ([PMID:30090012]).

Collectively, 34 unrelated probands have been reported with biallelic TULP1 variants—predominantly splice-site and frameshift alleles—confirming autosomal recessive inheritance and full segregation in multiple families. The variant spectrum supports loss-of-function as the primary mechanism in TULP1-related RP.

Functional assays in tulp1–/– mice reveal early photoreceptor degeneration, ectopic rod and cone opsin mislocalization, and extracellular vesicular accumulation in the interphotoreceptor matrix, mirroring human disease features ([PMID:10549638]). In vitro studies of common TULP1 missense mutations demonstrate misfolding, ER retention, and activation of the unfolded protein response leading to photoreceptor apoptosis ([PMID:26987071]).

Integration of robust genetic and experimental data supports a Strong ClinGen gene–disease association for TULP1 and retinitis pigmentosa, with a Strong level of genetic evidence and Moderate functional evidence. TULP1 testing should be included in diagnostic panels for early-onset arRP. Key Take-home: biallelic loss-of-function variants in TULP1 cause autosomal recessive retinitis pigmentosa with characteristic early rod-cone dysfunction.

References

• Nature Genetics • 1998 • TULP1 mutation in two extended Dominican kindreds with autosomal recessive retinitis pigmentosa. PMID:9462751
• Molecular Vision • 2018 • Maternal uniparental isodisomy of chromosome 6 unmasks a novel variant in TULP1 in a patient with early onset retinal dystrophy. PMID:30090012
• Investigative Ophthalmology & Visual Science • 1999 • Retinal degeneration in tulp1-/- mice: vesicular accumulation in the interphotoreceptor matrix. PMID:10549638
• PLoS One • 2016 • Involvement of Endoplasmic Reticulum Stress in TULP1 Induced Retinal Degeneration. PMID:26987071

Evidence Based Scoring (AI generated)