PLOD2 – Bruck syndrome type 2

PLOD2 encodes lysyl hydroxylase 2, essential for collagen cross-linking. Biallelic pathogenic variants in PLOD2 underlie autosomal recessive Bruck syndrome type 2, characterized by congenital joint contractures and bone fragility. Clinical presentations range from prenatal lethal bent bones to classical Bruck syndrome with normal mineralization. Genetic testing identifies biallelic missense, nonsense, frameshift, and splice-site variants, confirming diagnosis and guiding prognosis.

Genetic analyses in at least 15 unrelated probands ([PMID:29178448]) demonstrate consistent autosomal recessive inheritance. Identified variants include nonsense (eg, c.2038C>T (p.Arg680Ter)), frameshift, and splice-site changes, leading to loss-of-function of LH2. Compound heterozygous and homozygous genotypes segregate with disease in multiple siblings, reinforcing pathogenicity. No additional affected relatives beyond probands were reported.

Functional assays corroborate a loss-of-function mechanism. Patient fibroblasts with c.2038C>T show markedly reduced PLOD2 expression and impaired collagen post-translational modification ([PMID:33664768]). Mouse embryonic fibroblasts lacking FKBP65, a PLOD2 cofactor, display deficient hydroxylysine-aldehyde-derived cross-links, phenocopying LH2 deficiency and rescuable by wild-type LH2 reconstitution ([PMID:28378777]).

Further cellular studies of the p.Arg619His variant reveal significant downregulation of PLOD2 protein and mislocalization in HEK293T cells, aligning with reduced enzymatic activity and supporting variant pathogenicity ([PMID:35601416]). These experimental data confirm that impaired LH2 function underlies the Bruck syndrome phenotype.

Integration of extensive genetic and functional evidence supports a Strong gene–disease relationship according to ClinGen criteria. Testing for PLOD2 variants is recommended for patients with congenital contractures and unexplained bone fragility. Identification of biallelic PLOD2 loss-of-function variants enables definitive diagnosis and informs genetic counseling.

Key Take-Home: Biallelic PLOD2 loss-of-function variants cause autosomal recessive Bruck syndrome type 2, and comprehensive genetic testing combined with functional assays ensures accurate diagnosis and management.

References

• Journal of bone and mineral research • 2018 • Expanding the Clinical Spectrum of Phenotypes Caused by Pathogenic Variants in PLOD2. PMID:29178448
• Human Mutation • 2012 • Mutations in PLOD2 cause autosomal-recessive connective tissue disorders within the Bruck syndrome--osteogenesis imperfecta phenotypic spectrum. PMID:22689593
• Scientific reports • 2017 • FKBP65-dependent peptidyl-prolyl isomerase activity potentiates the lysyl hydroxylase 2-driven collagen cross-link switch. PMID:28378777
• Frontiers in genetics • 2021 • Case Report: Exome Sequencing Identified a Novel Compound Heterozygous Variation in PLOD2 Causing Bruck Syndrome Type 2. PMID:33664768
• Frontiers in pediatrics • 2022 • Genetic Analysis and Functional Study of a Pedigree With Bruck Syndrome Caused by PLOD2 Variant. PMID:35601416

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