Type I and Type II Keratins: Classification, Pairing, and Clinical Implications
Keratin Classification
Keratins are intermediate filament proteins divided into two distinct families: Type I (acidic) keratins and Type II (basic-to-neutral) keratins, which must pair together as obligate heteropolymers to form functional cytoskeletal filaments in epithelial cells. 1, 2
Type I Keratins (Acidic)
- 28 genes encoding acidic keratins located on chromosome 17 3, 4
- Smaller molecular weight proteins
- Must pair with Type II keratins to form functional filaments 1, 2
Type II Keratins (Basic-to-Neutral)
- 26 genes encoding basic-to-neutral keratins located on chromosome 12q13 3, 4
- Larger molecular weight proteins
- Eight Type II keratin genes are clustered together at 12q13, with their organization reflecting evolutionary relationships 3
Keratin Pairing Patterns
Stratified Epithelia (Skin)
In stratified epithelia, the primary keratin pair expressed in basal keratinocytes is K5 (Type II) and K14 (Type I). 5
- Basal layer: K5/K14 pair provides mechanical stability to basal keratinocytes 5
- Suprabasal layers: K1 (Type II) and K10 (Type I) pair in differentiated keratinocytes 1
- Palmoplantar epidermis: K9 (Type I) pairs with K1 in thick skin 1
- Hair follicles: Approximately half of all 54 functional keratin genes are restricted to various hair follicle compartments 4
Simple Epithelia (Internal Organs)
In simple epithelia of digestive organs, K8 (Type II) and K18 (Type I) form the primary keratin pair. 6, 3
- K8/K18 expressed in liver, pancreas, and intestinal epithelium 6
- These genes are located adjacent to each other in the Type II keratin cluster on chromosome 12 3
Clinical Implications of Keratin Mutations
Epidermolysis Bullosa Simplex (EBS) - Basal Type
Mutations in K5 (KRT5) or K14 (KRT14) genes cause basal EBS, resulting in intraepidermal blistering within basal keratinocytes due to cellular fragility. 5
- Mechanism: Dominant-negative mutations disrupt keratin filament cytoskeleton, making cells less resilient to mechanical trauma 1
- Clinical subtypes:
- Inheritance: Autosomal dominant in most cases 1, 4
Epidermolytic Hyperkeratosis (Bullous Congenital Ichthyosiform Erythroderma)
Mutations in K1 or K10 genes cause suprabasal keratinocyte fragility with abnormal keratin filament clumping in differentiated layers. 1
- Blistering occurs above the basal layer due to suprabasal keratin pair dysfunction 1
Epidermolytic Palmoplantar Keratoderma
Mutations in K9 (Type I) or K1 (Type II) cause thickened, fragile skin on palms and soles. 1
- K9 is specifically expressed in palmoplantar epidermis 1
Pachyonychia Congenita
Mutations in K6a, K6b, K16, or K17 cause nail dystrophy, palmoplantar keratoderma, and oral leukokeratosis. 1
- These keratins are expressed in specific epithelial compartments including nail beds 1
Digestive System Disorders
Mutations in K8 or K18 predispose to cryptogenic cirrhosis and increase susceptibility to liver injury. 1, 6
Key Clinical Pitfalls
Dominant-Negative Effect
Most keratin mutations act in a dominant-negative manner, meaning the mutant protein disrupts the function of normal keratin proteins, making gene therapy challenging. 1
- Simply adding normal keratin genes is insufficient; the mutant gene must be inactivated 1
Tissue-Specific Expression
The clinical phenotype depends entirely on which keratin pair is mutated, as keratins are expressed in tissue- and differentiation-specific patterns. 2, 4
- K5/K14 mutations affect stratified epithelia (skin blistering) 5
- K8/K18 mutations affect simple epithelia (liver disease) 6
- K1/K10 mutations affect suprabasal epidermis (ichthyosis) 1
Prenatal Diagnosis
For severe keratin disorders, prenatal diagnosis from chorionic villus samples is available using genomic DNA mutation detection methods. 1