KRT86 and monilethrix

KRT86 (HGNC:6463) is robustly linked to monilethrix (MONDO_0008009), a rare autosomal dominant disorder characterized primarily by hair fragility, patchy alopecia, and follicular hyperkeratosis (PMID:19400537). Multiple independent studies have documented affected families exhibiting vertical transmission of the disease, with clinical presentations that include both complete and incomplete penetrance. The clinical evaluations, including microscopic hair analysis, have consistently supported a diagnosis of monilethrix in patients carrying KRT86 mutations. This association has been reinforced by detailed genetic studies that pinpoint deleterious variants in critical regions of the gene. The recurring identification of specific mutations across diverse ethnic backgrounds further supports the causative role of KRT86.

In the first investigative report, a large Turkish consanguineous family with 11 affected individuals was studied, and a heterozygous mutation was identified. Segregation analysis in this family clearly demonstrated the transmission of the mutation along with the phenotype (PMID:19400537). The study emphasizes that even with variable expressivity, the genetic alteration in KRT86 is a key driver of the clinical phenotype. Such robust segregation data are crucial in supporting the gene–disease relationship.

Additional case reports from diverse populations have consistently identified the missense variant c.1204G>A (p.Glu402Lys) in the KRT86 gene. For instance, studies published in The British Journal of Dermatology (PMID:22670615) and the Chinese Medical Journal (PMID:23981620) have reported this variant in families with monilethrix. The recurrence of this specific mutation across independent cohorts, combined with the observation of incomplete penetrance in some cases, underscores its utility as a diagnostic marker for the disease.

Multi-patient studies have further illuminated the variant spectrum associated with monilethrix. One study from Annales de Genetique (PMID:15050877) detailed the co-occurrence of mutations in KRT86 and related keratin genes, highlighting genotype–phenotype correlations that range from severe localized hair defects to milder, generalized presentations. These findings support the clinical relevance of genetic testing for KRT86 variants in suspected cases of monilethrix.

From a mechanistic perspective, although detailed functional assays are limited in the supplied evidence, the known role of KRT86 in maintaining hair shaft integrity provides a strong biological rationale for its involvement in monilethrix. The pathogenic mechanism likely involves a dominant-negative effect whereby the mutated keratin protein disrupts the normal assembly of the hair cortex. The accumulation of multiple independent lines of genetic evidence, along with the consensus on autosomal dominant inheritance, provides a coherent narrative that bolsters the clinical utility of molecular diagnostics in this condition.

Key take‑home: KRT86 mutation testing, especially for recurrent variants such as c.1204G>A (p.Glu402Lys), is critical for confirming a diagnosis of monilethrix and guiding clinical decision‑making.

References

• Genetic counseling (Geneva, Switzerland) • 2009 • Pitfalls of mapping a large Turkish consanguineous family with vertical monilethrix inheritance PMID:19400537
• The British journal of dermatology • 2012 • A novel monilethrix mutation in coil 2A of KRT86 causing autosomal dominant monilethrix with incomplete penetrance PMID:22670615
• Chinese medical journal • 2013 • Mutation detection of type II hair cortex keratin gene KRT86 in a Chinese Han family with congenital monilethrix PMID:23981620
• Clinical and experimental dermatology • 2015 • A novel KRT86 mutation in a Turkish family with monilethrix, and identification of maternal mosaicism PMID:25809918
• Skin research and technology • 2023 • Gene detection in a family with monilethrix and treatment with 5% topical minoxidil PMID:36382623
• Annales de genetique • 2004 • A study of phenotypic correlation with the genotypic status of HTM regions of KRTHB6 and KRTHB1 genes in monilethrix families of Indian origin PMID:15050877

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