HKDC1 – Autosomal Recessive Retinitis Pigmentosa

Identification of the hexokinase domain containing 1 (HKDC1) gene as a candidate for autosomal recessive retinitis pigmentosa (RP) emerged from whole-exome sequencing of 68 unresolved RP probands. Two unrelated families harbored a homozygous missense variant in HKDC1, implicating this gene in late-onset retinal degeneration and extending the molecular spectrum of RP beyond the established 70 genes. (PMID:30085091)

Genetic analysis revealed a rare, highly conserved homozygous variant, c.173C>T (p.Thr58Met), absent in 4000 ethnically matched controls and multiple population databases, consistent with a recessive mode of inheritance. This single missense change was detected in two probands from separate pedigrees, supporting segregation with disease. (PMID:30085091)

Segregation data are limited to the two probands in independent families but show co-segregation of the homozygous variant with RP. No additional unrelated variants or recurrent alleles have been reported to date. The variant spectrum currently comprises a single missense alteration in HKDC1 associated with RP. (PMID:30085091)

Functional assays demonstrated that mutant HKDC1 protein exhibits partial loss of hexokinase enzymatic activity in vitro, indicating a hypomorphic effect. Endogenous Hkdc1 is expressed in mouse retina, localizes to photoreceptor inner segments, and is essential for normal photoreceptor function. (PMID:30085091)

In vivo, CRISPR/Cas9-generated Hkdc1 knockout mice lacking retinal HKDC1 expression showed reduced scotopic electroretinogram responses, thinning of the outer nuclear layer, and mislocalization of rhodopsin to inner segments and rod cell bodies, recapitulating key features of human RP. (PMID:30085091)

Together, genetic and functional data support a loss-of-function mechanism for HKDC1 in autosomal recessive RP. While additional families and variants will strengthen the evidence, current findings provide a compelling basis for diagnostic screening of HKDC1 in unexplained RP cases. Key take-home: HKDC1 should be included in gene panels for autosomal recessive retinitis pigmentosa.

References

• Human molecular genetics • 2018 • Whole-exome sequencing revealed HKDC1 as a candidate gene associated with autosomal-recessive retinitis pigmentosa. PMID:30085091

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