Division of Plastic and Reconstructive Surgery, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
Am J Med Genet A. 2010 Mar;152A(3):770-6. doi: 10.1002/ajmg.a.33317.
Craniometaphyseal dysplasia is caused by mutations in ANKH (ankylosis, progressive homolog [mouse]) in the majority of cases, and all of the reported mutations are single amino acid changes. Genomic DNA from an affected patient, his biological parents, and a sibling was amplified and ANKH was sequenced. The affected patient had a complex heterozygous mutation in exon 7 (c.936T > C, c.938C > G, c.942_953delTGGTTGACGGAA), predicting p.Try290Gln and p.Trp292_Glu295del. We studied the effect of the predicted mutation on the subcellular distribution of ANKH protein. Immunofluorescent labeling of COS-7 cells transduced with normal or mutant Ank (murine progressive ankylosis), showed that normal Ank localized to both the plasma membrane and cytoplasm, whereas mutant Ank was detected only in the cytoplasmic compartment. We propose that this craniometaphyseal dysplasia mutation causes a loss of ANKH protein expression and activity in the plasma membrane as a result of aberrant intracellular protein trafficking.
颅骨干骺发育不良多数情况下是由ANKH（ankylosis，渐进同源物[小鼠]）基因突变引起的，所有报道的突变均为单个氨基酸改变。扩增受累患者、其亲生父母和同胞的基因组 DNA 并对 ANKH 进行测序。受累患者在 7 号外显子（c.936T > C、c.938C > G、c.942_953delTGGTTGACGGAA）中存在复杂杂合突变，预测 p.Try290Gln 和 p.Trp292_Glu295del。我们研究了预测突变对 ANKH 蛋白亚细胞分布的影响。用正常或突变的 Ank（鼠渐进性强直性）转导的 COS-7 细胞进行免疫荧光标记，结果表明正常 Ank 定位于质膜和细胞质，而突变的 Ank 仅在细胞质中检测到。我们推测这种颅骨干骺发育不良突变导致 ANKH 蛋白表达和质膜活性丧失，这是由于异常的细胞内蛋白运输所致。
