PCYT1A – Spondylometaphyseal Dysplasia with Cone-Rod Dystrophy

Spondylometaphyseal dysplasia with cone-rod dystrophy is a rare autosomal-recessive skeletal dysplasia characterized by severe short stature, lower-limb bowing, platyspondyly and early‐onset retinal degeneration. The disease arises from biallelic loss-of-function or missense mutations in PCYT1A, which encodes the rate-limiting CTP:phosphocholine cytidylyltransferase α (CCTα) of the Kennedy phosphatidylcholine biosynthesis pathway. Affected individuals present with growth failure in infancy and progressive visual impairment due to cone-rod dystrophy, underscoring the crucial role of phosphatidylcholine homeostasis in both cartilage and retinal health.

Genetic analyses of four affected individuals from two consanguineous Brazilian families revealed homozygous PCYT1A variants segregating with disease in an autosomal-recessive pattern (4 probands, 2 families) (PMID:24387991). No heterozygous carriers exhibited clinical features, and segregation was fully concordant in both pedigrees. These studies reported one frameshift variant and one missense change, each occurring in the catalytic domain of CCTα. Parental and sibling genotyping confirmed co-segregation of homozygosity with disease status without phenotypic heterogeneity.

The variant spectrum comprises one frameshift mutation and one missense mutation in the catalytic domain of CCTα. The missense allele c.385G>A (p.Glu129Lys) affects a conserved catalytic residue, while c.968dup (p.Ser323fsTer?) predicts premature truncation of CCTα (PMID:24387991). No recurrent or founder alleles have been described beyond these families. Population databases show these variants are absent or extremely rare, consistent with a fully penetrant recessive mechanism.

Functional assessment in patient-derived fibroblasts and overexpression systems demonstrated that disease-linked PCYT1A variants destabilize the catalytic core, reduce thermostability and impair enzymatic kinetics in vitro. In vitro assays showed reduced substrate affinity (increased Km for CTP) and aberrant folding of mutant CCTα proteins, confirming a loss-of-function mechanism (PMID:30559292). Rescue of wild-type activity in reconstitution experiments restored normal kinetic parameters, supporting a direct causal link between enzyme dysfunction and disease pathology.

A retina-specific Pcyt1a knockout mouse model recapitulated key ocular features of human SMD-CRD, including progressive photoreceptor degeneration, loss of Müller glial cells and reduced scotopic electroretinogram responses. Proteomic and lipidomic profiling revealed dysregulated fatty acid metabolism and activation of ferroptosis pathways in knockout retinas, indicating a non-redundant role for CCTα in retinal lipid homeostasis (PMID:38858683). These in vivo data align with human phenotypes and further validate the pathogenic impact of PCYT1A deficiency on retinal integrity.

Collectively, genetic and functional data establish a strong causal association between biallelic PCYT1A variants and spondylometaphyseal dysplasia with cone-rod dystrophy. The autosomal-recessive inheritance, segregation in multiple families, absence of conflicting reports and concordant biochemical and animal model findings satisfy ClinGen criteria for a Strong gene–disease relationship. Key Take-home: PCYT1A should be included in genetic testing panels for skeletal dysplasia and early-onset retinal degeneration to enable definitive diagnosis and guide patient management.

References

• American journal of human genetics • 2014 • Mutations in PCYT1A cause spondylometaphyseal dysplasia with cone-rod dystrophy. PMID:24387991
• The Journal of biological chemistry • 2019 • Disease-linked mutations in the phosphatidylcholine regulatory enzyme CCTα impair enzymatic activity and fold stability PMID:30559292
• BMC Biology • 2024 • PCYT1A deficiency disturbs fatty acid metabolism and induces ferroptosis in the mouse retina. PMID:38858683

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