Alternative titles; symbols
HGNC Approved Gene Symbol: PLOD1
SNOMEDCT: 25606004;
Cytogenetic location: 1p36.22 Genomic coordinates (GRCh38): 1:11,934,717-11,975,537 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 1p36.22 | Ehlers-Danlos syndrome, kyphoscoliotic type, 1 | 225400 | Autosomal recessive | 3 |
Lysyl hydroxylase (EC 1.14.11.4) catalyzes the formation of hydroxylysine in collagens and other proteins with collagen-like amino acid sequences, by the hydroxylation of lysine residues in X-lys-gly sequences. The enzyme is a homodimer consisting of subunits with a molecular mass of about 85 kD. No significant homology has been found between the primary structures of lysyl hydroxylase and the 2 types of subunits of prolyl-4-hydroxylase (176710, 176790) despite the marked similarities in kinetic properties between these 2 collagen hydroxylases. The hydroxylysine residues formed in the lysyl hydroxylase reaction have 2 important functions: first, their hydroxy groups serve as sites of attachment for carbohydrate units, either the monosaccharide galactose or the disaccharide glucosylgalactose; and second, they are essential for the stability of the intermolecular collagen crosslinks (summary by Hautala et al., 1992).
Hautala et al. (1992) isolated and characterized cDNA clones for lysyl hydroxylase from a human placenta lambda-gt11 cDNA library. The clones encode a polypeptide of 709 amino acid residues and a signal peptide of 18 amino acids. The human coding sequence shows 72% identity to the chick sequences at the nucleotide level and 76% identity at the amino acid level. The C-terminal region is especially well conserved; residues 588 to 727 show 94% identity between the 2 species and residues 639 to 715 show 99% identity.
Yeowell et al. (1992) also isolated a cDNA for lysyl hydroxylase. Hybridization of Northern blots of fibroblast RNA isolated from 12 unrelated patients with kyphoscoliotic Ehlers-Danlos syndrome (EDSKSCL1; 225400) showed in 2 patients an additional mRNA which may represent a mutation responsible for their lysyl hydroxylase deficiency.
Hautala et al. (1992) mapped the gene encoding lysyl hydroxylase, symbolized PLOD (for procollagen-lysine, 2-oxoglutarate 5-dioxygenase), to chromosome 1 by Southern blot analysis of human/mouse somatic cell hybrids, to the 1pter-p34 region by use of cell hybrids that contained various rearrangements of human chromosome 1, and to 1p36.3-p36.2 by in situ hybridization. Thus, the PLOD gene not only shows no similarity to prolyl-4-hydroxylase (despite similarities in kinetic properties) but also is not linked to the genes for the alpha and beta subunits of that enzyme, which are located on chromosomes 10 and 17, respectively.
Studying recombinant inbred strains, McClive and Morahan (1994) assigned the mouse homolog, Plod, to chromosome 4.
Heikkinen et al. (1994) isolated genomic clones for the PLOD gene and determined that it contains 19 exons and a 5-prime flanking region with characteristics shared by housekeeping genes. A constitutive expression of the gene in different tissues suggested that lysyl hydroxylase has an essential function. From sequencing the introns where many mutations and rearrangements had been found to be concentrated, they demonstrated extensive homology of intron 9 and intron 16 resulting from the many Alu sequences contained therein. Intron 9 contained 5 and intron 16 contained 8 Alu sequences. The high homology in many short identical or complementary sequences in these introns appeared to generate many potential recombination sites within the gene.
Yeowell and Walker (2000) stated that at least 20 different mutations had been identified in the PLOD1 gene that result in kyphoscoliotic Ehlers-Danlos syndrome (EDSKSCL1; 225400), previously designated EDS VI (EDS6). Two of these mutations, a large duplication of exons 10-16, arising from a homologous recombination of intronic Alu sequences (153454.0002), and a nonsense mutation, Y511X (153454.0007), in exon 14, had been identified in 5 or more unrelated patients. Both mutations appeared to have originated from a single ancestral gene. Alternative processing pathways involving alternate splicing and mRNA degradation, which reduce the effect of the mutant allele and restore partial activity of lysyl hydroxylase, had been identified.
Because the clinical features of Nevo syndrome were similar to those of EDS VI, Giunta et al. (2005) studied 7 patients with the disorder, 2 of whom had previously been reported by Al-Gazali et al. (1997) and 1 by Hilderink and Brunner (1995). Six patients were homozygous for an arg319-to-ter mutation in the PLOD1 gene (R319X; 153454.0001) and 1 patient was homozygous for a large deletion comprising exon 17 of PLOD1 (153454.0006). Giunta et al. (2005) concluded that Nevo syndrome is clinically indistinguishable from EDS VI and presented evidence that increased length at birth and wrist drop, in addition to muscular hypotonia and kyphoscoliosis, should prompt the physician to consider EDS VI earlier than had previously been the case.
Grillos et al. (2022) reported the first case of warmblood fragile foal syndrome type 1 (WFFS) in a Thoroughbred, which was caused by homozygosity for the same mutation in the PLOD1 gene (c.2032G-A, G678R) known to cause the disorder in warmbloods. Additionally, the foal was determined to have normal alleles for another EDS-like equine syndrome known as hereditary equine regional dermal asthenia (HERDA). WFFS is an autosomal recessive equine disorder previously reported in only warmblood horses with this point mutation. Foals born with this condition have collagen dysplasia and typically present with an open abdomen, extensive cutaneous lesions, very thin skin, abnormal flexibility of distal joints, flexed carpal and tarsal joints, and deformed spinal cord. The Thoroughbred foal was born prematurely at 309 days gestation (normal equine gestation is 340 days). During delivery, the foal's skin was noted to be fragile and tore easily from the forelimbs, a large hematoma was noted on the foal's neck, and spinal scoliosis was present. The foal was euthanized immediately after delivery. Postmortem examination revealed multiple cutaneous defects with separation of the skin at the level of the deep dermis and superficial fascia and scoliosis. Both distal hindlimbs had laxity and were hyperextensible. Both carpal joints were mildly contracted with inability to fully extend. Grillos et al. (2022) postulated that since the carrier frequency of the PLOD1 variant in adult Thoroughbreds is 2.4%, other cases likely exist in the breed and are either not reported or are lost early in embryonic development. Grillos et al. (2022) suggested that the disease be renamed 'fragile fatal syndrome type 1 (FFS) since the mutation is not exclusively identified in warmblood breeds and a clinical case is now confirmed in Thoroughbred horses.
In 2 sisters with kyphoscoliotic Ehlers-Danlos syndrome (EDSKCL1; 225400), Hyland et al. (1992) identified homozygosity for a single basepair substitution converting arginine-319 (CGA) to a stop codon (TGA) (arg319 to ter; R319X). The healthy parents, who were first cousins, and 2 of 3 healthy sibs were heterozygous. The mutation led to almost complete absence of lysyl hydroxylase activity in extracts derived from fibroblasts of the patients. Steinmann et al. (1993) described the 2 sisters, who were from Qatar, in some detail and included illustrations (see their Figure 15, p. 376). They showed characteristic features including bluish sclerae, myopia, astigmatism, and microcornea. Both were floppy as infants with poor cry, difficulty in sucking, and delayed motor development. In both, extensive neuromuscular workup was negative. Kyphoscoliosis was present in each at birth; in the elder sister, severe and progressive spinal deformity required insertion of a rod at the age of 7 years. Steinmann et al. (1993) commented that the younger sister was much more mildly affected, thus illustrating intrafamilial variability. Steinmann et al. (1995) reported in these sibs an altered urinary ratio of lysyl pyridinoline:hydroxylysyl pyridinoline which is characteristic of EDS6. Since their mutation eliminates the enzyme's highly conserved C-terminal half, believed to be responsible for the binding of the ferrous-ion cofactor, and thus should result in a complete lack of activity (Hyland et al., 1992), it is therefore unknown how pyridinoline cross-links are formed in the absence of lysyl hydroxylase. The most plausible explanation is the existence of the predicted but still hypothetical N-telopeptide-specific lysyl hydroxylase (Royce and Barnes, 1985).
In 6 patients from 5 families originating from the United Arab Emirates with Nevo syndrome, 2 of whom had been reported by Al-Gazali et al. (1997), Giunta et al. (2005) identified the R319X mutation. In all 6 patients, Giunta et al. (2005) identified cosegregation of a 30111G-A polymorphism in intron 13 with the disease-related mutation in cis, suggesting a founder effect. The polymorphism was not found in association with the R319X mutation in the 2 sibs from Qatar.
In cells from 2 sisters with kyphoscoliotic Ehlers-Danlos syndrome (EDSKSCL1; 225400) in whom Pinnell et al. (1972) first demonstrated reduced lysyl hydroxylase activity, Hautala et al. (1993) demonstrated homozygosity for a duplication of nucleotides 1176 to 1955, corresponding to amino acids 326 to 585 in the normal sequence. mRNA for PLOD produced in the affected cells was about 4 kb in size, whereas it was 3.2 kb in the control cells. From Southern blotting data, the duplicated region of the gene was estimated to be about 6 to 9 kb and corresponded to 7 exons.
Studying fibroblast cultures established from skin biopsies 20 years previously, Pousi et al. (1994) reported the identical mutation in a 49-year-old female shown to have hydroxylysine-deficient skin collagen by Sussman et al. (1974). In addition to loose jointedness, stretchable and fragile skin, bruisability, and acrocyanosis, the patient had severe scoliosis and serious ocular complications ending in complete detachment of the retina bilaterally. A brother likewise sustained bilateral retinal detachment after minor trauma and his sister was totally blind. The parents and 3 children of the brother were normal (McKusick, 1972). Pousi et al. (1994) could show that the duplication in this and the family reported by Hautala et al. (1993) was caused by an Alu-Alu recombination. Pousi et al. (1994) cloned the junction fragment of the duplication, which allowed synthesis of appropriate primers for rapid screening for this rearrangement in other families with type VI EDS. The mutation was apparently homozygous; simple-sequence-repeat-polymorphism analysis did not support uniparental isodisomy inheritance in either of the 2 families.
The 7-exon duplication in PLOD was shown to be 8.9 kb and to be caused by an Alu-Alu recombination in introns 9 and 16 of the gene (Pousi et al., 1994). The duplication did not disturb the splicing of introns, and sequencing of the cDNA for lysyl hydroxylase from the affected cells revealed a lengthened mRNA containing the nucleotides for amino acids 326 to 585 duplicated in tandem. The apparent homozygosity of this duplication in 2 unrelated families with nonconsanguineous parents suggested that the mutation might be found in other EDS6 families. Using PCR, Heikkinen et al. (1997) analyzed 26 additional EDS6 families from various countries and found that 7 of them had this duplication. Their data indicated a frequency of 19.1% for this mutant allele among 35 EDS6 families studied. Haplotype analysis showed a variation in the sequence of the DNA region surrounding the duplication.
Yeowell (1999) found this duplication of 7 exons on the maternal allele and an R670X nonsense mutation (153454.0010) on the paternal allele in a then 5-year-old boy with severe kyphosclerotic EDS. Prenatal diagnosis showed heterozygosity for only the R670X mutation in the fetus, predicting an unaffected offspring.
In a male of Mexican-American ancestry with kyphoscoliotic Ehlers-Danlos syndrome (EDSKSCL1; 225400), who was born to a nonconsanguineous couple, Ha et al. (1994) found compound heterozygosity for mutations in the PLOD gene: a 2056G-A transition, resulting in a gly678-to-arg (G678R) substitution in a highly conserved region of the enzyme on the paternal allele, and a 3-bp deletion (1618_1620del), resulting in loss of residue glu532 (153454.0003) on the maternal allele. Neither parent had clinical evidence of EDS. The patient was born full term without premature rupture of fetal membranes. He was noted at birth to exhibit hemifacial asymmetry and dislocation of the right wrist and hip. Other features characteristic of type VI Ehlers-Danlos syndrome (EDS6; 225400) included myopia, hyperextensible and velvety skin, and hypotrophic wound healing. Bilateral herniorrhaphy and orchidopexy were performed at the age of 6 months, and Harrington rod placement for kyphoscoliosis at the age of 3 years. He was demonstrated to be ascorbate-responsive and did well from the age of 6 to approximately 14 years when he stopped taking ascorbate. These features were reported by Dembure et al. (1984, 1987), Elsas et al. (1978), and Miller et al. (1979). At the age of 15 years, he had spontaneous arterial rupture in the upper thigh. Bilateral venous thrombosis resulted from compression stasis which required fasciotomies. Pharmacologic amounts of ascorbate (5.0 g/d) were reinstituted and wound healing progressed normally. Amino acid analysis of the skin showed zero hydroxylysine per 1,000 residues with normal values being 5 per 1,000. Assay of lysyl hydroxylase activity in cultured dermal fibroblasts showed that the patient had a ratio of lysyl hydroxylase to prolyl hydroxylase that was 24% of the control values. An autosomal recessive mode of inheritance was deduced from the same assay performed on his parents' dermal fibroblasts, which showed 52% and 86% lysyl hydroxylase activity relative to prolyl hydroxylase activity, in the father and mother, respectively.
For discussion of the 3-bp deletion (1618_1620del) in the PLOD1 gene that was found in compound heterozygous state in a patient with kyphoscoliotic Ehlers-Danlos syndrome (EDSKSCL1; 225400) by Ha et al. (1994), see 153454.0003.
In a patient with kyphoscoliotic Ehlers-Danlos syndrome (EDSKSCL1; 225400) with markedly reduced lysyl hydroxylase activity, Pousi et al. (1998) found compound heterozygosity for a deletion mutation and a splicing defect in the PLOD gene. Northern analysis of RNA isolated from skin fibroblasts of the patient demonstrated truncated lysyl hydroxylase mRNA. PCR and sequence analysis confirmed the truncation and indicated that the cells contained 2 types of shortened mRNAs, 1 lacking sequence corresponding to exon 16 and the other lacking sequence corresponding to exon 17. Analysis of genomic DNA showed deletion of the penultimate adenosine from the 3-prime end of intron 15 of 1 allele. This defect appeared to be responsible for skipping of exon 16 sequences from the transcript. The other allele, inherited from the mother, contained an Alu-Alu recombination with deletion of about 3,000 bp, including exon 17 (153454.0006). The identified mutations in exon 16 and exon 17 did not alter the reading frame of the transcripts.
For discussion of the 3-kb deletion in the PLOD1 gene that was found in compound heterozygous state in a patient with kyphoscoliotic Ehlers-Danlos syndrome (EDSKSCL1; 225400) by Pousi et al. (1998), see 153454.0005.
In a patient with Nevo syndrome, who was previously reported by Hilderink and Brunner (1995), Giunta et al. (2005) identified homozygosity for deletion of exon 17 of the PLOD1 gene. The patient was the offspring of first cousins in the Netherlands; at birth, he was noted to have excessive length and was very hypotonic, requiring ventilation for a few minutes. He also presented volar edema of the hands and feet, spindle-shaped fingers, a narrow thorax, dorsiflexion contractures of the feet, thoracolumbar scoliosis, and hypermobility of the wrists, described as wrist drop. Marfan syndrome (154700) was suspected because of his marfanoid habitus. At age 7 weeks his length was greater than the 97th centile and he had generalized muscular hypotonia and severe thoracic kyphosis. Up to the age of 13 years no ocular complications had occurred; however, the patient had moderate myopia (-3 diopters) and microcornea (9 mm bilaterally). The aorta was normal by ultrasound. Frequent middle ear infections had been a main health problem, requiring middle ear operation for cholesteatoma at age 11 years. At the age of 12 years his height was 170 cm (4 cm above the 97th centile) and his arm span was 117 cm.
In a patient with kyphoscoliotic Ehlers-Danlos syndrome (EDSKSCL1; 225400), Yeowell and Walker (1997) found compound heterozygosity, with a pathogenetic mutation in each PLOD allele contributing to a very low level of mRNA and lysyl hydroxylase activity in fibroblasts. One allele contained a paternally inherited 1557C-G transition that converted codon 511 from tyrosine to a stop codon (Y511X) and introduced an NheI restriction site in exon 14 of the PLOD gene. The mutation in the other allele was an exon 5 deletion that produced a shortened PCR transcript and generated a premature stop codon at the beginning of exon 7. Sequencing of genomic DNAs spanning exon 5 showed a mutation in the consensus donor splice site at the beginning of intron 5 (gt to at) in both the proband and his mother (153454.0008). By means of RT-PCR, the parents' fibroblasts showed a disproportionately lower level of each mutant allele compared to the normal alleles. In a subsequent pregnancy, the fetus was correctly predicted to be clinically normal by the finding of heterozygosity for only the mother's splice site mutation by study of chorionic villus cells taken at 10 weeks of gestation (Yeowell and Walker, 1999).
In another patient with severe kyphoscoliotic EDS, Walker et al. (1999) found the Y511X mutation in homozygous state. The autosomal recessive nature of the disorder was verified by the fact that the mother, who had 1 mutated and 1 normal allele, was clinically unaffected.
For discussion of the splice site mutation in the PLOD1 gene that was found in compound heterozygous state in a patient with kyphoscoliotic Ehlers-Danlos syndrome (EDSKSCL1; 225400), by Yeowell and Walker (1997), see 153454.0007.
In 2 of 3 patients with kyphoscoliotic Ehlers-Danlos syndrome (EDSKSCL1; 225400), Brinckmann et al. (1998) found the relatively common 8.9-kb duplication (153454.0002) in the PLOD1 gene. In the third patient, they identified a G-to-C transversion at nucleotide 2036, resulting in a substitution of tryptophan by cysteine in the highly conserved C-terminal region of the enzyme (W612C). The mother was heterozygous for the mutation; a null mutation was thought to have occurred in the allele inherited from the father. The patient, a male, had muscular hypotonia, kyphoscoliosis, and habitual shoulder luxation present from birth. Hypermobility of joints and cutaneous hyperextensibility were moderate. The skin showed atrophic scars, and microcornea was present. He had a stroke at the age of 15 years.
In a 5-year-old boy with severe kyphoscoliotic Ehlers-Danlos syndrome (EDSKSCL1; 225400), Yeowell (1999) identified compound heterozygosity for mutations in the PLOD1 gene: an arg670-to-ter (R670X) mutation inherited from the father, and a duplication of 7 exons inherited from the mother (153454.0002).
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