PLOD1 – Kyphoscoliotic Ehlers-Danlos Syndrome (EDS VI)

Ehlers-Danlos syndrome, kyphoscoliotic type 1 (formerly EDS VI) is a rare autosomal recessive connective tissue disorder characterized by early-onset kyphoscoliosis, severe muscle hypotonia, generalized joint hypermobility, skin fragility, and ocular manifestations. The underlying defect is a deficiency of lysyl hydroxylase 1, encoded by PLOD1, which catalyzes the posttranslational hydroxylation of lysine residues in collagen. Biallelic pathogenic variants in PLOD1 result in reduced hydroxylysine content, defective collagen cross-linking, and the clinical EDS VI phenotype.

Genetic evidence includes case series of 9 unrelated probands across 7 families presenting compound heterozygous or homozygous PLOD1 variants ([PMID:9617436]; [PMID:10874315]). All patients inherited variants in trans consistent with autosomal recessive inheritance, and parental carrier status was confirmed by identification of single heterozygous alleles without phenotypic involvement. Recurrent alleles such as c.1533C>G (p.Tyr511Ter) and duplication of exons 10–16 have been observed in multiple independent families, suggesting founder effects for certain variants ([PMID:11001813]).

The variant spectrum comprises at least 20 distinct PLOD1 mutations, including nonsense (e.g., c.1533C>G (p.Tyr511Ter)), splice-site (c.579+1G>A), frameshift, missense (c.1836G>C (p.Trp612Cys)), and large duplication alleles. The missense variant c.1836G>C (p.Trp612Cys) lies in the conserved C-terminal region and abolishes enzyme activity when expressed in cell models, while nonsense and splice variants result in truncated or exon-skipped transcripts.

Functional studies demonstrate markedly reduced lysyl hydroxylase activity in patient fibroblasts and recombinant systems. Expression of mutant LH1 constructs in insect cells shows loss of enzymatic function for missense and cysteine-deletion mutants, and fibroblast assays reveal decreased hydroxylysine content and abnormal collagen mobility. Rescue of activity by wild-type PLOD1 confirms a loss-of-function mechanism ([PMID:15854030]; [PMID:11001813]).

No studies have reported conflicting genetic evidence or association with alternative phenotypes. The overall body of genetic and experimental data meets ClinGen criteria for a Strong gene–disease association, with robust genetic segregation and concordant functional assays.

Key Take-home: PLOD1 sequencing and deletion/duplication analysis are clinically useful for confirming autosomal recessive kyphoscoliotic EDS and guiding genetic counseling, prenatal diagnosis, and management of vascular and skeletal complications.

References

• Archives of Dermatological Research • 1998 • Ehlers-Danlos syndrome type VI: lysyl hydroxylase deficiency due to a novel point mutation (W612C). PMID:9617436
• Human Mutation • 2000 • Mutational analysis of the lysyl hydroxylase 1 gene (PLOD) in six unrelated patients with Ehlers-Danlos syndrome type VI: prenatal exclusion of this disorder in one family. PMID:10874315
• The Journal of Investigative Dermatology • 2005 • A novel mutation in the lysyl hydroxylase 1 gene causes decreased lysyl hydroxylase activity in an Ehlers-Danlos VIA patient. PMID:15854030
• Molecular Genetics and Metabolism • 2000 • Mutations in the lysyl hydroxylase 1 gene that result in enzyme deficiency and the clinical phenotype of Ehlers-Danlos syndrome type VI. PMID:11001813

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