title: Novel ANKH mutation in a patient with sporadic craniometaphyseal dysplasia.
abstract: 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.
authors.affiliation: Division of Plastic and Reconstructive Surgery, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Allison
authors.initials: A
authors.lastname: Zajac
authors.forename: Seung-Hak
authors.initials: SH
authors.lastname: Baek
authors.forename: Imad
authors.initials: I
authors.lastname: Salhab
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Radecki
authors.forename: Sukwha
authors.initials: S
authors.lastname: Kim
authors.forename: Hakon
authors.initials: H
authors.lastname: Hakonarson
authors.forename: Hyun-Duck
authors.initials: HD
authors.lastname: Nah
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000844:Ankylosis / Q000235:genetics; D001483:Base Sequence; D019556:COS Cells; D002648:Child; D002522:Chlorocebus aethiops; D004252:DNA Mutational Analysis; D006579:Heterozygote; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D020125:Mutation, Missense; D010009:Osteochondrodysplasias / Q000235:genetics*; D010641:Phenotype; D028061:Phosphate Transport Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D017384:Sequence Deletion
chemical_list: C498770:ANKH protein, human; D028061:Phosphate Transport Proteins; D011993:Recombinant Fusion Proteins