PLOD2 – Bruck syndrome

Bruck syndrome (MONDO:0017195) is an autosomal recessive connective tissue disorder characterized by bone fragility akin to osteogenesis imperfecta and congenital joint contractures. PLOD2 (HGNC:9082) encodes lysyl hydroxylase 2 (LH2), a key enzyme for telopeptide lysine hydroxylation in type I collagen. Deficiency of LH2 impairs collagen cross-link formation, leading to bone fragility and contracture phenotypes.

Genetic evidence supports a definitive gene–disease relationship. A total of 26 probands (PMID:15523624; PMID:22689593; PMID:29177700) from at least 13 independent families harbor biallelic PLOD2 variants with autosomal recessive segregation. Five additional affected relatives have been documented with concordant genotypes across multiple consanguineous pedigrees.

To date, 15 unique PLOD2 variants have been reported, including 8 missense substitutions (e.g., c.1856G>A (p.Arg619His)), 4 protein-truncating alleles (nonsense or frameshift), and 3 splice-site mutations. These cluster within the catalytic domain of LH2, suggesting a mutational hotspot underlying enzymatic loss of function.

Functional assays in patient‐derived cells demonstrate that missense variants such as p.Arg619His markedly reduce PLOD2 protein levels and collagen I production, despite increased mRNA expression, confirming a loss‐of‐function mechanism (PMID:35601416).

A Plod2fs/fs mouse model carrying the human c.1559dupC frameshift allele recapitulates key features of Bruck syndrome, including joint contractures, absent extensor tendons, and deficient type I collagen telopeptide hydroxylation in developing bone (PMID:39088537).

Clinically, patients present with recurrent fractures (HP:0002757), congenital contractures (HP:0002803), scoliosis (HP:0002650), pterygia, and occasional cardiac or pulmonary complications. Collagen cross-link analysis in urine and targeted PLOD2 sequencing enable definitive diagnosis.

Key Take-home: Biallelic PLOD2 variants cause Bruck syndrome via LH2 haploinsufficiency, with strong genetic and functional evidence supporting diagnostic testing for early interventions.

References

• American journal of medical genetics. Part A • 2004 • Phenotypic and molecular characterization of Bruck syndrome (osteogenesis imperfecta with contractures of the large joints) caused by a recessive mutation in PLOD2. PMID:15523624
• Human mutation • 2012 • Mutations in PLOD2 cause autosomal-recessive connective tissue disorders within the Bruck syndrome--osteogenesis imperfecta phenotypic spectrum. PMID:22689593
• Calcified tissue international • 2018 • Novel Mutations in PLOD2 Cause Rare Bruck Syndrome. PMID:29177700
• Frontiers in pediatrics • 2022 • Genetic Analysis and Functional Study of a Pedigree With Bruck Syndrome Caused by PLOD2 Variant. PMID:35601416
• American journal of medical genetics. Part A • 2023 • Expanding the phenotype of Bruck syndrome: Severe limb deformity, arthrogryposis, congenital cardiac disease and pulmonary hemorrhage. PMID:36282022
• Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research • 2024 • Loss of the long form of Plod2 phenocopies contractures of Bruck syndrome-osteogenesis imperfecta. PMID:39088537
• International journal of molecular sciences • 2024 • Cellular and Molecular Effects of the Bruck Syndrome-Associated Mutation in the PLOD2 Gene. PMID:39769143

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