Olauson Hannes, Krajisnik Tijana, Larsson Charlotta, Lindberg Bengt, Larsson Tobias E
Department of Medical Sciences, Uppsala University Hospital, Ing.70, 3 tr, 75185 Uppsala, Sweden.
Eur J Endocrinol. 2008 Jun;158(6):929-34. doi: 10.1530/EJE-08-0011. Epub 2008 Mar 5.
Hyperostosis-hyperphosphataemia syndrome (HHS) is a rare hereditary disorder characterized by hyperphosphataemia, inappropriately normal or elevated 1,25-dihydroxyvitamin D(3) and localized painful cortical hyperostosis. HHS was shown to be caused by inactivating mutations in GALNT3, encoding UDP-N-acetyl-alpha-D-galactosamine: polypeptide N-acetylgalactosaminyltransferase 3 (GalNAc-transferase; GALNT3). Herein, we sought to identify the genetic cause of hyperphosphataemia and tibial hyperostosis in a 19-year-old girl of Colombian origin.
Genomic DNA was extracted and sequencing analysis of the GALNT3 and fibroblast growth factor 23 (FGF23) genes performed. Serum levels of intact and C-terminal FGF23 were measured using two different ELISA methods.
Mutational analysis identified a novel homozygous missense mutation in exon 6 of GALNT3 (1584 G>A), leading to an amino acid shift from Arg to His at residue 438 (R438H). The mutation was not found in over 200 control alleles or in any single nucleotide polymorphism databases. The R438 residue is highly conserved throughout species and in all known GalNAc-transferase family members. Modelling predicted the substitution deleterious for protein structure. Importantly, the phosphaturic factor FGF23 was differentially processed, as reflected by low intact (15 pg/ml) but high C-terminal (839 RU/ml) serum FGF23 levels.
We report on the first missense mutation in GALNT3 giving rise to HHS, since previous GALNT3 mutations in HHS caused aberrant splicing or premature truncation of the protein. The R438H substitution likely abrogates GALNT3 activity, in turn causing enhanced FGF23 degradation and subsequent hyperostosis/hyperphosphataemia.
骨质增生-高磷血症综合征（HHS）是一种罕见的遗传性疾病，其特征为高磷血症、1,25-二羟维生素D(3)水平正常或升高且不恰当，以及局限性疼痛性皮质骨增生。研究表明，HHS是由GALNT3基因的失活突变引起的，该基因编码UDP-N-乙酰-α-D-半乳糖胺：多肽N-乙酰半乳糖胺基转移酶3（GalNAc转移酶；GALNT3）。在此，我们试图确定一名19岁哥伦比亚裔女孩高磷血症和胫骨骨质增生的遗传原因。
提取基因组DNA，并对GALNT3和成纤维细胞生长因子23（FGF23）基因进行测序分析。使用两种不同的酶联免疫吸附测定（ELISA）方法测量血清中完整和C末端FGF23的水平。
突变分析在GALNT3的外显子6中鉴定出一个新的纯合错义突变（1584 G>A），导致第438位氨基酸从精氨酸转变为组氨酸（R438H）。在200多个对照等位基因或任何单核苷酸多态性数据库中均未发现该突变。R438残基在所有物种和所有已知的GalNAc转移酶家族成员中高度保守。模型预测该替代对蛋白质结构有害。重要的是，磷调节因子FGF23的加工方式不同，血清中完整FGF23水平较低（15 pg/ml）但C末端FGF23水平较高（839 RU/ml）即反映了这一点。
我们报告了GALNT3中首个导致HHS的错义突变，因为之前HHS中的GALNT3突变导致蛋白质异常剪接或过早截断。R438H替代可能消除了GALNT3的活性，进而导致FGF23降解增强以及随后的骨质增生/高磷血症。
