Mutation of a type II keratin gene (K6a) in pachyonychia congenita

Pachyonychia congenita (PC) is a rare autosomal dominant condition characterized by multiple ectodermal abnormalities¹⁻³. Patients with Jadassohn-Lewandowsky Syndrome (MIM 167200; PC-1) have nail defects (onchyogryposis), palmoplantar hyperkeratosis, follicular hyperkeratosis and oral leukokeratosis⁴. Those with the rarer Jackson-Lawler Syndrome (MIM 167210; PC-2) lack oral involvement but have natal teeth and cutaneous cysts⁵. Ultra-structural studies have identified abnormal keratin tonofilaments⁶ and linkage to the keratin gene cluster on chromosome 17 has been found in PC families⁷. Keratins are the major structural proteins of the epidermis and associated appendages and the nail, hair follicle, palm, sole and tongue are the main sites of constitutive K6, K16 and K17 expression⁸⁻¹⁰. Furthermore, mutations in K16 and K17 have recently been identified in some PC patients¹¹. Although we did not detect K16 or K17 mutations in PC families from Slovenia, we have found a heterozygous deletion in a K6 isoform (K6a) in the affected members of one family. This 3 bp deletion (AAC) in exon 1 of K6a removes a highly conserved asparagine residue (N170) from position 8 of the 1A helical domain (N8). This is the first K6a mutation to be described and this heterozygous K6a deletion is sufficient to explain the pathology observed in this PC-1 family.

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