Bruck syndrome 2 variant lacking congenital contractures and involving a novel compound heterozygous PLOD2 mutation

Mumm, Steven; Gottesman, Gary S.; Wenkert, Deborah; Campeau, Philippe M.; Nenninger, Angela; Huskey, Margaret; Bijanki, Vinieth N.; Veis, Deborah J.; Barnes, Aileen M.; Marini, Joan C.; Stolina, Marina; Zhang, Fan; McAlister, William H.; Whyte, Michael P.

doi:10.1016/j.bone.2019.115047

Cited by 20 publications

(37 citation statements)

References 33 publications

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“…As a rare but typical example of recessive OI, most cases of BRKS are distinguished by congenital joint contractures and pterygia, albeit with several exceptions (Tham et al, 2018 ; Mumm et al, 2020 ). Currently, two BRKS subtypes, BRKS1 and BRKS2, with almost identical phenotypes but different pathogenesis are recognized (van der Slot et al, 2003 ; Alanay et al, 2010 ).…”

Section: Discussionmentioning

confidence: 99%

“…Currently, two BRKS subtypes, BRKS1 and BRKS2, with almost identical phenotypes but different pathogenesis are recognized (van der Slot et al, 2003 ; Alanay et al, 2010 ). To our knowledge, 25 constitutional mutations in PLOD2 associating with BRKS2-like phenotypes have been detected in fewer than 20 studies, showing significant C-terminal aggregation ( Figure 2B ; Supplementary Table 1 ) (Mumm et al, 2020 ). In this study, a compound heterozygous variation in the PLOD2 gene with two variants, c.2038C>T and c.191_201+3del, was identified and confirmed.…”

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…To our knowledge, fewer than 20 studies have reported the BRKS2 cases with respect to defects in PLOD2 (Mumm et al, 2020 ). Moreover, the genotype-phenotype correlation of BRKS2 is not fully established, owing to the low amount and relatively clustered distribution of constitutional variations in PLOD2 , the vague structural and functional delineation of the N-terminal of LH2 protein as well as the strong phenotypic variability of BRKS2 (Tham et al, 2018 ; Mumm et al, 2020 ). Furthermore, given the commonality of cell signaling pathways between BRKS2 and multiple types of cancers, the in-depth study of corresponding molecules would benefit scientific and clinical understanding in both fields (Guo et al, 2018 ; Wang et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

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Case Report: Exome Sequencing Identified a Novel Compound Heterozygous Variation in PLOD2 Causing Bruck Syndrome Type 2

Zhang

et al. 2021

Front. Genet.

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Bruck Syndrome (BRKS) is a rare type of recessive osteogenesis imperfecta (OI) and consists of two subtypes, BRKS1 and BRKS2, which are caused by variations in FKBP10 and PLOD2 genes, respectively. In this study, a family that had experienced multiple miscarriages and recurrent fetal skeletal dysplasia was recruited for the purpose of a multiplatform laboratory investigation. Prenatal genetic testing with whole-exome sequencing (WES) identified a compound heterozygous variation in the PLOD2 gene with two variants, namely c.2038C>T (p.R680*) and c.191_201+3 delATACTGTGAAGGTA (p.Y64Cfs*12). The amino acids affected by the two variants maintained conserved across species. And the result of immunohistochemistry (IHC) indicated that the expression of PLOD2 protein in the proband's osteochondral tissue was significantly decreased. These findings in our study expanded the variation spectrum of PLOD2 gene, provided solid evidence for the family's counseling in regard to future pregnancies, strongly supported the application of WES in prenatal diagnosis, and might give insight into the understanding of PLOD2 function.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Case Report: Exome Sequencing Identified a Novel Compound Heterozygous Variation in PLOD2 Causing Bruck Syndrome Type 2

Zhang

et al. 2021

Front. Genet.

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“…Bruck syndrome is a disorder characterized by joint flexion contractures and skeletal dysplasia that shows strong clinical overlap with OI but is caused by biallelic mutations in either the FKBP10 or the PLOD2 genes [160][161][162]. PLOD2 encodes lysyl hydroxylase 2 (LH2), the enzyme responsible for hydroxylation of collagen telopeptide lysine.…”

Section: Bone Extracellular Matrix Biophysical Properties In Osteogenmentioning

confidence: 99%

Deciphering the Relevance of Bone ECM Signaling

Alcorta-Sevillano

Macías

Infante

et al. 2020

Cells

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Bone mineral density, a bone matrix parameter frequently used to predict fracture risk, is not the only one to affect bone fragility. Other factors, including the extracellular matrix (ECM) composition and microarchitecture, are of paramount relevance in this process. The bone ECM is a noncellular three-dimensional structure secreted by cells into the extracellular space, which comprises inorganic and organic compounds. The main inorganic components of the ECM are calcium-deficient apatite and trace elements, while the organic ECM consists of collagen type I and noncollagenous proteins. Bone ECM dynamically interacts with osteoblasts and osteoclasts to regulate the formation of new bone during regeneration. Thus, the composition and structure of inorganic and organic bone matrix may directly affect bone quality. Moreover, proteins that compose ECM, beyond their structural role have other crucial biological functions, thanks to their ability to bind multiple interacting partners like other ECM proteins, growth factors, signal receptors and adhesion molecules. Thus, ECM proteins provide a complex network of biochemical and physiological signals. Herein, we summarize different ECM factors that are essential to bone strength besides, discussing how these parameters are altered in pathological conditions related with bone fragility.

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Full‐Length Human Collagen Lysyl Hydroxylases

Scietti

Forneris

2020

Encyclopedia of Inorganic and Bioinorganic Chemistry

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Procollagen lysyl hydroxylases and glycosyltransferases (LH, also known as procollagen lysyl‐2‐oxoglutarate dioxygenases (PLOD)) are essential biosynthesis enzymes present in all collagen‐containing organisms, from sponges to humans. Higher vertebrates present three separate PLOD genes encoding for distinct enzyme isoforms (LH1, LH2a/b, and LH3), sharing ∼70% amino acid sequence identity. The LH1 and LH2 isoforms exclusively display Fe 2+ , 2‐oxoglutarate‐dependent lysyl 5‐hydroxylase activity, whereas LH3 is a multifunctional enzyme, able to further catalyze the Mn 2+ ‐dependent β‐(1, O )‐galactosylation and the subsequent α‐(1,2)‐glucosylation of 5‐hydroxylysines. Despite exclusive selectivity for lysine residues within collagenous polypeptides, little is known about the specificity of LH enzymes for different amino acid sequences in different collagen types: LH1 and LH3 isoforms act on collagen triple‐helical regions, whereas the LH2 isoform specifically hydroxylates collagen telopeptides, yet no consensus sequences, nor minimum sequence lengths, have been proposed as requirements for catalysis. Available crystal structures of full‐length human LH3 show an elongated homodimeric quaternary structure, with three aligned domains constituting each enzyme's polypeptide: the N‐terminal glycosyltransferase (GT) domain, a central noncatalytic accessory (AC) domain, and a C‐terminal lysyl hydroxylase (LH) domain. Dimerization occurs in the C‐terminal domain, in proximity to the LH catalytic site. Dimerization is indeed essential for LH activity, but is dispensable for the glycosyltransferase activities of LH3.

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Bruck syndrome 2 variant lacking congenital contractures and involving a novel compound heterozygous PLOD2 mutation

Cited by 20 publications

References 33 publications

Case Report: Exome Sequencing Identified a Novel Compound Heterozygous Variation in PLOD2 Causing Bruck Syndrome Type 2

Case Report: Exome Sequencing Identified a Novel Compound Heterozygous Variation in PLOD2 Causing Bruck Syndrome Type 2

Deciphering the Relevance of Bone ECM Signaling

Full‐Length Human Collagen Lysyl Hydroxylases

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