骨质疏松症的合成代谢治疗选择仍然有限。发现新的合成代谢药物靶标的一种方法是鉴定极端高骨量(HBM)的遗传原因。我们在英国HBM研究中调查了一个无法解释的HBM谱系,全国先证者与HBM及其亲属的队列。HBM家族的全外显子组测序(WES)鉴定出一种罕见的杂合错义变体(NM_004482.4:c.1657C>T,p.Arg553Trp)在GALNT3中,适当分离。对英国HBM研究和盎格鲁-澳大利亚骨质疏松遗传学联合会(AOGC)的数据进行的询问显示,与HBM无关的个体具有另一种罕见的杂合变体(NM_004482.4:c.831T>A,p.Asp277Glu)在同一基因内。计算机蛋白质模型预测p.Arg553Trp会破坏盐桥相互作用,导致GALNT3不稳定;p.Asp277Glu会破坏锰结合,从而破坏GALNT3的催化功能。双等位基因功能丧失GALNT3突变改变FGF23代谢,导致高磷血症并引起家族性肿瘤钙质沉着症(FTC)。然而,FTC病例的骨密度(BMD),当报告时,要么正常,要么低。GALNT3位点的常见变异显示出与腰椎的全基因组显著关联,股骨颈,和全身BMD。然而,在编码FGF23,其受体FGFR1或共受体klotho的位点,未观察到与BMD显著相关.孟德尔随机化分析,使用来自原代人成骨细胞的表达数量性状基因座(eQTL)数据和来自英国生物库的GWAS数据,提示GALNT3的表达增加会降低全身,腰椎和股骨颈骨密度,但对磷酸盐浓度没有影响。总之,GALNT3中罕见的杂合功能丧失变体可能导致HBM而不改变磷酸盐浓度。这些发现表明,GALNT3可能通过FGF23调节以外的途径影响BMD,对其的鉴定可能会产生骨质疏松症的新的合成代谢药物靶标。
Anabolic treatment options for osteoporosis remain limited. One approach to discovering novel anabolic drug targets is to identify genetic causes of extreme high bone mass (HBM). We investigated a pedigree with unexplained HBM within the UK HBM study, a national cohort of probands with HBM and their relatives. Whole exome sequencing (WES) in a family with HBM identified a rare heterozygous missense variant (NM_004482.4:c.1657C > T, p.Arg553Trp) in
GALNT3, segregating appropriately. Interrogation of data from the UK HBM study and the Anglo-Australasian Osteoporosis Genetics Consortium (AOGC) revealed an unrelated individual with HBM with another rare heterozygous variant (NM_004482.4:c.831 T > A, p.Asp277Glu) within the same gene. In silico protein modeling predicted that p.Arg553Trp would disrupt salt-bridge interactions, causing instability of
GALNT3, and that p.Asp277Glu would disrupt manganese binding and consequently
GALNT3 catalytic function. Bi-allelic loss-of-function
GALNT3 mutations alter FGF23 metabolism, resulting in hyperphosphatemia and causing familial tumoral calcinosis (FTC). However, bone mineral density (BMD) in FTC cases, when reported, has been either normal or low. Common variants in the
GALNT3 locus show genome-wide significant associations with lumbar, femoral neck, and total body BMD. However, no significant associations with BMD are observed at loci coding for FGF23, its receptor FGFR1, or coreceptor klotho. Mendelian randomization analysis, using expression quantitative trait loci (eQTL) data from primary human osteoblasts and genome-wide association studies data from UK Biobank, suggested increased expression of GALNT3 reduces total body, lumbar spine, and femoral neck BMD but has no effect on phosphate concentrations. In conclusion, rare heterozygous loss-of-function variants in GALNT3 may cause HBM without altering phosphate concentration. These findings suggest that GALNT3 may affect BMD through pathways other than FGF23 regulation, the identification of which may yield novel anabolic drug targets for osteoporosis. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).