KLHL7 – Retinitis Pigmentosa

Autosomal dominant retinitis pigmentosa (adRP) was first linked to KLHL7 through a six-generation Scandinavian pedigree in which a heterozygous c.449G>A (p.Ser150Asn) variant was identified at the RP42 locus ([PMID:19520207]). Subsequent mutation screening of 502 probands revealed three missense variants across six independent families, all clustering in the conserved BACK domain ([PMID:19520207]).

An expanded series characterized five unrelated adRP patients with two novel KLHL7 variants, c.472T>C (p.Cys158Arg) and c.433A>G (p.Asn145Asp), demonstrating hyperautofluorescent ring formation and progressive outer retinal atrophy on SW-AF and NIR-AF imaging ([PMID:31856884]).

In one extended family of 11 affected individuals, the c.458C>T (p.Ala153Val) allele segregated in seven affected relatives over 17 years, revealing slowly progressive rod–cone dysfunction with preserved night vision into late life ([PMID:20547956]).

Biallelic loss-of-function in KLHL7, exemplified by homozygous c.1051C>T (p.Arg351Ter), causes an early-onset syndromic retinal dystrophy overlapping Bohring–Opitz and Crisponi syndromes; two siblings exhibited mid-peripheral hypopigmented lesions and bull’s-eye maculopathy ([PMID:30997404]).

Functional assays demonstrate that KLHL7 forms a Cul3-based E3 ubiquitin ligase and that adRP-causative BACK-domain missense variants selectively disrupt Cul3 binding, attenuating ubiquitin ligase activity in a dominant-negative manner and leading to substrate accumulation ([PMID:21828050]).

Collectively, strong genetic evidence from 12 unrelated adRP probands, segregation in seven relatives, and concordant functional data support a dominant-negative mechanism for KLHL7-mediated RP. KLHL7 should be included in adRP diagnostic panels, and mechanistic insights inform potential targeted therapies. Key take-home: Heterozygous KLHL7 variants cause autosomal dominant RP via dominant-negative disruption of E3 ligase function.

References

• American journal of human genetics • 2009 • Mutations in a BTB-Kelch protein, KLHL7, cause autosomal-dominant retinitis pigmentosa. PMID:19520207
• Orphanet journal of rare diseases • 2019 • Novel mutations in the 3-box motif of the BACK domain of KLHL7 associated with nonsyndromic autosomal dominant retinitis pigmentosa. PMID:31856884
• Archives of ophthalmology • 2010 • Phenotype associated with mutation in the recently identified autosomal dominant retinitis pigmentosa KLHL7 gene. PMID:20547956
• BMJ open ophthalmology • 2019 • New macular findings in individuals with biallelic KLHL7 gene mutation. PMID:30997404
• The Journal of biological chemistry • 2011 • Ubiquitin ligase activity of Cul3-KLHL7 protein is attenuated by autosomal dominant retinitis pigmentosa causative mutation. PMID:21828050

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