TULP1 – Leber congenital amaurosis

TULP1 encodes a photoreceptor-specific protein involved in polarized transport of nascent opsins to the outer segments of rod and cone cells. Biallelic pathogenic variants in TULP1 underlie autosomal recessive Leber congenital amaurosis (LCA), the earliest and most severe form of inherited retinal dystrophy.

Evidence from single‐patient case reports identified novel homozygous truncating variants (c.1081C>T (p.Arg361Ter)) in a consanguineous LCA pedigree using whole exome sequencing ([PMID:24547928]). A second report revealed uniparental isodisomy of chromosome 6 unmasking a homozygous frameshift c.524dupC (p.Pro176ThrfsTer7) in TULP1 with clinical features of congenital nystagmus and night blindness ([PMID:30090012]).

In a cohort of 179 unrelated LCA patients, TULP1 mutations accounted for 1.7% of disease alleles, identified in three probands from familial and sporadic cases ([PMID:15024725]). More recently, a multi‐center study of 17 patients described eight missense, six nonsense, one in-frame deletion, and two splice‐site TULP1 variants, confirming substantial allelic heterogeneity and corroborating biallelic pathogenicity in LCA and related retinal dystrophies ([PMID:36769033]).

The variant spectrum spans loss-of-function alleles (nonsense and frameshift) and deleterious missense substitutions clustering in the tubby domain. No recurrent or founder variants have been reported, reflecting ethnic diversity in mutation distribution.

Functional studies support a loss-of-function mechanism. Tulp1^-/- mice develop early rod and cone degeneration with mislocalized opsins and accumulation of extracellular vesicles in the interphotoreceptor matrix ([PMID:10549638]). In vitro, common TULP1 missense variants (e.g., p.Arg420Leu, p.Ile459Lys, p.Phe491Leu) misfold and accumulate in the endoplasmic reticulum, triggering unfolded protein response (PERK and IRE1 activation, CHOP upregulation) and photoreceptor apoptosis ([PMID:26987071]).

No studies have disputed the association of TULP1 with LCA; variant segregation aligns perfectly with disease status in consanguineous and outbred families, and phenotypic overlap with early-onset retinitis pigmentosa has been documented.

Integration of genetic and experimental findings confirms a strong gene–disease relationship: autosomal recessive TULP1 deficiency disrupts photoreceptor protein trafficking, leading to irreversible congenital visual impairment. Additional evidence, including in vivo rescue studies, would further cement a definitive classification.

Key Take-home: TULP1‐related LCA is a recessive photoreceptor trafficking disorder with consistent genotype–phenotype correlations and a clear loss-of-function mechanism, informing molecular diagnosis and future therapeutic strategies.

References

• Ophthalmic genetics • 2015 • Advantage of Whole Exome Sequencing over Allele-Specific and Targeted Segment Sequencing in Detection of Novel TULP1 Mutation in Leber Congenital Amaurosis. PMID:24547928
• 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
• Human mutation • 2004 • Leber congenital amaurosis: comprehensive survey of the genetic heterogeneity, refinement of the clinical definition, and genotype-phenotype correlations as a strategy for molecular diagnosis. PMID:15024725
• PLoS One • 2016 • Involvement of Endoplasmic Reticulum Stress in TULP1 Induced Retinal Degeneration. PMID:26987071
• Investigative ophthalmology & visual science • 1999 • Retinal degeneration in tulp1-/- mice: vesicular accumulation in the interphotoreceptor matrix. PMID:10549638
• International journal of molecular sciences • 2023 • Biallelic Variants in TULP1 Are Associated with Heterogeneous Phenotypes of Retinal Dystrophy. PMID:36769033

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