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, while 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 due to aberrant intracellular protein trafficking.

Two novel large ANKH deletion mutations in sporadic cases with craniometaphyseal dysplasia

“…These novel 18 and 12 base pair in-frame deletions are the largest ANKH mutations causing CMD identified to date, in addition to the recently identified complex mutation of two missense point mutations and a 12-bp deletion (3). All other previously identified mutations were inframe deletions of a single amino acid, an insertion of one amino acid due to a splicing defect, or amino acid substitutions due to point mutations (1,2,4).…”

Maternal mosaicism of an ANKH mutation in a family with craniometaphyseal dysplasia

“…All of the previously identified mutations of ANKH were in‐frame deletions of amino acids, an insertion of one amino acid due to a splicing defect, and a substitution of an amino acid due to a point mutation (Table ). Recently, a case of a complex missense mutation and a 12 bp deletion was reported . Of note, two ANKH mutations in exon 9 (Ser375del and Phe377del) are supposed to be hot spot mutations in CMD, because both mutations were found in a total of four families reported so far (Table ), with Ser375del being found in the present patient.…”

“…Recently, a case of a complex missense mutation and a 12 bp deletion was reported. 6 Of note, two ANKH mutations in exon 9 (Ser375del and Phe377del) are supposed to be hot spot mutations in CMD, because both mutations were found in a total of four families reported so far (Table 1), with Ser375del being found in the present patient. The sequences of ANKH c.1120_1131 consist of short tandem repeats of (TTC) (TCC) (TTC) (TTC), so the slipped strand mispairing during DNA replication may cause the 3 bp deletion of ANKH hot spot mutations.…”

Rapid degradation of progressive ankylosis protein (ANKH) in craniometaphyseal dysplasia

“…Mutations associated with the autosomal dominant form of CMD have been identified in the progressive ankylosis gene ( ANKH ) 8 , 9 . Mutations in the ANKH gene that are linked to CMD occur mostly within the C-terminal region of the protein resulting in single amino acid substitutions or insertions or in frame deletions 8 – 11 . Mutations in the N-terminal ANKH are most commonly associated with another disorder known as calcium pyrophosphate dehydrate deposition disease (CPPDD) 12 .…”