DSTYK – Hereditary Spastic Paraplegia 23

Autosomal-recessive hereditary spastic paraplegia 23 (SPG23) presents with early‐onset lower limb spastic paraparesis and diffuse skin and hair dyspigmentation at birth, with progressive patchy pigment loss during childhood. SPG23 maps to chromosome 1q24–q32 in consanguineous Middle Eastern pedigrees and is clinically distinguished by combined neurodegeneration and pigmentary defects.

Genome‐wide linkage and whole‐exome sequencing in a Palestinian–Jordanian family identified a complex homozygous 4-kb deletion/20-bp insertion in DSTYK (c.2467+930_*1895delinsTGTAGTCCTGCTCCTTGAGG) removing the last two exons and part of the 3′ UTR in all four affected siblings ([PMID:28157540]). The identical DSTYK deletion segregated in two additional Arab-Israeli families, yielding ten affected individuals from three unrelated pedigrees ([PMID:28157540]). These data fulfill strong autosomal-recessive segregation criteria with a recurrent loss-of-function allele.

To date, SPG23 has been associated exclusively with a single recurrent DSTYK LoF deletion; no missense or splice variants have been reported in affected individuals. Segregation of the homozygous deletion in multiple families provides robust genetic evidence of causality.

Functional studies on patient skin biopsies demonstrated markedly reduced DSTYK protein levels and focal melanocyte loss. Ultrastructural analysis revealed swollen mitochondria and cytoplasmic vacuoles in melanocytes, keratinocytes, and fibroblasts. Patient‐derived keratinocytes and fibroblasts—and Dstyk knockdown in mouse cells—showed increased ultraviolet-induced cell death and loss of kinase activity upon fibroblast growth factor stimulation, consistent with a haploinsufficiency mechanism ([PMID:28157540]).

Although DSTYK loss-of-function variants have been implicated as low-penetrance risk factors for congenital anomalies of the kidney and urinary tract (CAKUT), epilepsy, and amyotrophic lateral sclerosis in large cohorts and mouse models ([PMID:37746849]), these studies do not conflict with the definitive role of homozygous DSTYK deletions in SPG23.

Together, the genetic and functional data provide strong evidence that biallelic DSTYK loss of function causes SPG23. Key take-home: DSTYK should be included in diagnostic testing panels for autosomal-recessive spastic paraplegia with pigmentary skin anomalies.

References

• American journal of human genetics • 2017 • Large Intragenic Deletion in DSTYK Underlies Autosomal-Recessive Complicated Spastic Paraparesis, SPG23. PMID:28157540
• Genetics in Medicine • 2023 • Mouse and human studies support DSTYK loss of function as a low-penetrance and variable expressivity risk factor for congenital urinary tract anomalies. PMID:37746849

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