Novel mutation in LRP5 gene cause rare osteosclerosis: cases studies and literature review

Abstract

To study the effects of low-density lipoprotein receptor-related protein 5 (LRP5) gene mutations on bone, and to open up our view of LRP5 and Wnt pathways on bone mass regulation. Three patients with increased bone mineral density or thickened bone cortex were included, who were 30-year-old, 22-year-old and 50-year-old men, respectively. The latter two patients were son and father of a same family. The characteristics of bone X-rays were evaluated in detail. Bone turnover markers were detected, such as procollagen type 1 amino-terminal peptide (P1NP), alkaline phosphatase (ALP), and type 1 collagen carboxyl terminal peptide (β-CTX). Dual energy X-ray absorptiometry (DXA) was used to measure the bone mineral density (BMD) at lumbar spine and proximal femur of the patients. The targeted next-generation sequencing (NGS) technology was used to detect pathogenic gene mutations, which were further verified by Sanger sequencing. Moreover, the gene mutation spectrum and phenotypic characteristics of reported patients with LRP5 gain-of-function mutations were summarized by reviewing the literature. The main characteristics of the first patient were headache, facial paralysis, high BMD (lumbar vertebrae 1–4: 1.877 g/cm2, Z-score: 5.8; total hip: 1.705 g/cm2, Z-score: 5.7), slightly increased P1NP (87.0 ng/mL) and β-CTX (0.761 ng/mL) level, and with thickened bone cortex, especially the cranial vault. The latter two patients showed enlargement of the mandible and enlarged osseous prominence of the tours palatinus. X-rays showed that the bone cortex of skull and long bones were thickened. The bone turnover markers and BMD were normal. All three cases carried novel missense mutations in LRP5 gene, which were mutation in exon 3 (c.586 T > G, p.Trp196Gly) of the first patient, and mutation in exon 20 (c.4240C > A, p.Arg1414Ser) of the latter two patients. Combined with the reported literature, a total of 19 gain-of-function mutations in LRP5 were detected in 113 patients from 33 families. Hotspot mutations included c.724G > A, c.512G > T and c.758C > T. Furthermore, mutations in the exon 3 of LRP5 may cause severe phenotypes. LRP5 gain-of-function mutations can lead to rare autosomal dominant osteosclerosis type Ι (ADO Ι), which was characterized by increased bone mass and thickened bone cortex. In-depth research on the Wnt pathway will be benefit for discovering important mechanisms of bone mass regulation.

LRP5, Bone Mass Polymorphisms and Skeletal Disorders

“…Since then, a body of literature has emerged describing patients with the LRP5 variant-related high bone mass trait (Figure 5). A 2023 case report and review article by Zhao et al summarized the clinical characteristics reported for 113 patients with LRP5-activating variants (Table 1) [52]. Among the 43 cases they examined for which lumbar spine BMD data were available, 40 patients (93%) had Z-scores greater than 2.5, indicating that they had BMD scores at the 99th percentile compared to age-and sex-matched norms [52].…”

“…A 2023 case report and review article by Zhao et al summarized the clinical characteristics reported for 113 patients with LRP5-activating variants (Table 1) [52]. Among the 43 cases they examined for which lumbar spine BMD data were available, 40 patients (93%) had Z-scores greater than 2.5, indicating that they had BMD scores at the 99th percentile compared to age-and sex-matched norms [52]. Furthermore, 51 out of 57 cases (90%) that were assessed for mandible enlargement were found to have this phenotype [52], which is consistent with the previous work conducted by Gregson and Duncan who reviewed the body of literature on patients with LRP5 variant-related high bone mass phenotypes and also found this to be a prominent characteristic [53].…”

LRP5 high bone mass (Worth-type autosomal dominant endosteal hyperostosis): case report and historical review of the literature

“…On the other hand, we included papers written in 2002 or later only if LRP5 gene analysis was performed. According to these parameters, we included 155 patients (74 males and 81 females) described in 32 case reports published in the literature [ 4 – 8 , 16 , 18 – 22 , 24 , 25 , 27 – 42 , 42 – 44 ], including our patient herein described. Sixty-four patients (41%) out of these 155 underwent genetic analysis of the LRP5 gene and can be considered as being affected by LRP5 HBM.…”

“…Notably, one study recently reported the first missense mutation (R1414S) affecting a domain other than the first β-propeller domain of LRP5. The R1414S is in exon 20, which codes for the cytoplasmic domain of the LRP5 co-receptor protein; this affects the downstream release of β-catenin and thus can also determine HBM [ 42 ]. The different LRP5 mutations and all the reports in which they were detected are listed in Table 2 .…”

“…All mutations are missense except for one case of in-frame insertion of two residues (Roetzer et al, 2018 [ 38 ]). All mutations affect exons 2–4 except for LRP5 R1414S (Zhao et al, 2023 [ 42 ]), located in exon 20 coding for the cytoplasmic domain of the protein Case report Year Mutation Exon Little et al [ 25 ] 2002 LRP5 G171V Exon 3 Boyden et al [ 33 ] 2002 LRP5 G171V Exon 3 Van Weesenbeck et al [ 23 ] 2003 LRP5 A242T (referring to Beals et al (2001) [ 46 ]) LRP5 A214V (referring to Renton et al (2002) [ 21 ]) Exon 4 Exon 3 Boyden et al [ 44 ] 2004 LRP5 G171V LRP5 N198S Exon 3 Exon 3 Whyte MP et al [ 43 ] 2004 LRP5 G171V Exon 3 Kwee et al [ 22 ] 2005 LRP5 A214T Exon 3 Rickels et al [ 34 ] 2005 LRP5 R154M Exon 2 Balemans et al [ 39 ] 2007 LRP5 M282V Exon 4 Wang et al [ 35 ] 2013 LRP5 A242T Exon 4 Gregson et al [ 36 ] 2016 LRP5 N198S LRP5 A242T LRP5 R266C LRP5 T173M LRP5 Q89R Exon 3 Exon 4 Exon 2 Exon 3 Exon 2 Costantini et al [ 37 ] 2017 LRP5 N198Y Exon 3 Roetzer et al [ 38 ] 2018 ...…”