K6a-pEDD-PC

ABOUT THE KRT6A GENE

The KRT6A gene provides instructions for making a protein called keratin 6a or K6a. Keratins are a group of tough, fibrous proteins that form the structural framework of certain cells, particularly cells that make up the skin, hair, nails, and similar tissues. Keratin 6a is produced in the nails, the skin on the palms of the hands and soles of the feet, and the oral mucosa that lines the inside of the mouth.

Keratin 6a partners with a similar protein, keratin 16, to form molecules called keratin intermediate filaments. These filaments assemble into dense networks that provide strength and resilience to the skin, nails, and other tissues. Networks of keratin filaments protect these tissues from being damaged by friction and other everyday physical stresses. Keratin 6a is also among several keratins involved in wound healing.

Mutations in the KRT6A gene responsible for PC-K6a¹ change the structure of keratin 6a, preventing it from working effectively with keratin 16 and interfering with the assembly of the keratin intermediate filament network. Without this network, skin cells become fragile and are easily damaged, making the skin less resistant to friction and minor trauma. Even normal activities, such as walking can cause skin cells to break down, resulting in the formation of painful blisters and calluses. Additionally, fragile skin cells may abnormally produce more keratin in response to damage, which makes the skin problems worse.

Defective keratin 6a also disrupts the growth and function of cells in the nails and oral mucosa, which explains why the signs and symptoms of PC-K6a also affect these tissues. (Adapted from http://ghr.nlm.nih.gov/gene/KRT6A.)

¹PC classification replacing PC-1 and PC-2 classification. See W. H. McLean et al. The
phenotypic and molecular genetic features of pachyonychia congenita. J Invest Dermatol. 2011;131(5):1015-7.

To learn how many others have mutations in the same gene — or even the same specific mutation — visit the PC data page, which provides detailed information on those with PC and the various mutations.

Observations on PC-K6a from the IPCRR

Patients with mutations in PC-K6a experience painful plantar keratoderma as the most challenging feature of PC and are eager to find relief, especially for the associated pain.

• The condition is usually evident at birth, often presenting with 20/20 nail dystrophy.
  
• PC-K6a nails may be extremely thickened or may not grow out completely.
  
• Plantar keratoderma and pain is experienced by nearly 100% of PC-K6a patients by age 10. Pain levels for PC-K6a patients are often from 6 to 10 on a 0 to 10 scale.
  
• Leukokeratosis in oral mucosa is often present very early, and PC-K6a infants are often misdiagnosed with thrush.
  
• In children with PC-K6a, several unique conditions occur that are not typically seen in other types of PC:
  
  • Infants may have feeding/sucking problems with crying after a few seconds of sucking. This is solved by an enlarged hole in the nipple or use of syringe for feeding, or thickened formula. After initial crying, feeding usually can resume. Some infants undergo efforts by ENTs to remove the leukokeratosis which may make the condition worse and is not the cause of the feeding issue.
    
  • Follicular hyperkeratosis (FHK) is problematic for children up to age 12 or so and lessens after that time. It occurs at areas of friction on elbows, knees, waist, etc.
    
  • Extreme pain lasting 15 to 25 seconds occurs with first bite or first swallow, which we believe may be related to salivary glands is experienced by children ages 4 to 12 and lessens after that. This is often misdiagnosed as an ‘ear’ problem.

IPCRR Data for PC-K6a