Novel KRT83 and KRT86 mutations associated with monilethrix

Abstract

This study is unique in bringing together 12 affected individuals in three pedigrees one of which consisted of five generations. The affected individuals were all from three isolated villages within each other's vicinity (approximately 20-30 km distance from each other). Repeated use of common names in the different villages prompted us to consider the possibility that the population of different villages shared a common ancestor. Clinical findings in heterozygous carriersWhile documenting clinical features and family history, we noticed that some apparently unaffected individuals from affected families showed variable symptoms associated with the disease. After genetic testing of the families, it was evident that those people were genotypically heterozygous for the c.507delT mutation. For example, mother of Patient no. 6, an obligate heterozygous carrier of the mutation, experienced noticeable voice hoarseness in cold seasons. Thickening of the frenulum was also evident in mother of Patient no. 1. Although brother of Patient no. 7 seemed clinically normal, he had hoarseness and firm tongue and he also suffered from epilepsy. Thus, it is suggested that the physicians examining the presumably unaffected individuals in families with LP should consider heterozygous state of these individuals as an aetiologic factor contributing to their symptoms. AcknowledgementsWe would like to express our deep gratitude to our patients and their families. We could not have completed this study without excellent coordination of patients by Mrs. Rayat, the head of the health facility in one of the villages. Dr. Vida Yousefian assisted in coordination of patients for MRI and CT scans, and Dr. Marco Ajello provided interpretation of the neurological images. Authorship contributionLY and HV initiated the study, collected samples and performed the mutation analysis; MD, SA, HT, AK, CC-D and RM assisted in clinical evaluation of the patients; QL assisted in mutation analysis; JU wrote the paper; SA assisted in clinical evaluation; and MT directed the project. Conflict of interestsThe authors have no conflict of interests to declare. Supporting InformationAdditional supporting data may be found in the supplementary information of this article. Appendix S1. Clinical description of patients. Table S1. Summary of the clinical features of the 12 patients affected by lipoid proteinosis. Figure S1. Clinical features of the lipoid proteinosis patients. Figure S2. Brain CT scan and MRI. Monilethrix is an autosomal dominant hair disorder caused by mutations in the hard keratins KRT81, KRT83 and KRT86. The affected hairs are fragile and break easily, leading to scarring alopecia. Follicular hyperkeratosis in the neck and on extensor sides of extremities is a frequently associated finding. The disorder is rare, but probably underreported because its manifestations may be mild. Mutations in KRT81 and KRT86 are the most common. Here, we report new cases from Venezuela, the Netherlands, Belgium and France. The Venezuelan kindred is special for having...

Recessive progressive symmetric erythrokeratoderma results from a homozygous loss-of-function mutation ofKRT83and is allelic with dominant monilethrix

“…In contrast, heterozygous missense variants of KRT83 , c.1219G>A (p.Glu407Lys) and c.1252G>A (p.Glu418Lys), have been reported in two families with the autosomal dominant hair disorder, monilethrix (MIM 158000) 18 19. In the family segregating the p.Glu407Lys substitution, one of the three affected members additionally exhibited mild follicular hyperkeratosis.…”

Keratins: the hair shaft's backbone revealed

“…It is of special interest to note that we had the opportunity in the past to check the Venezuelan patients IV‐1 and IV‐2 reported in van Steensel et al. 's paper , who were not available for this study, and found the same mutation (c.1226T>C in KRT86 ) in these two sisters as well as in their father (Fig. S1).…”

“…Importance of keratins for hair shaft integrity and curvature. Mutations in keratins expressed in the distal part of the hair cortex, such as K81, K83 and K86, lead to moniltherix, which is characterized by fragile hair . This points to the fact that the hair cortex is mostly important for giving the strength to the hair shaft.…”

In search of hair damage using metabolomics?

“…However, they can and do reflect the life lived—as the fibre becomes a repository for various chemical moieties that result from cellular metabolism, pollution and metabolites of drugs as they pass from blood to cells in the follicle and remain sequestered in the hair fibre. Fibre morphology can also tell a story of hair damage and more rarely, genetics, as recently described by van Steensel et al . who discovered polymorphisms in two hair keratin genes KRT83 and KRT86 in monilethrix.…”

“…However, they can and do reflect the life livedas the fibre becomes a repository for various chemical moieties that result from cellular metabolism, pollution and metabolites of drugs as they pass from blood to cells in the follicle and remain sequestered in the hair fibre. Fibre morphology can also tell a story of hair damage and more rarely, genetics, as recently described by van Steensel et al8 who discovered polymorphisms in two hair keratin genes KRT83 and KRT86 in monilethrix. However, in cosmetic science, the relationship of fibre Commentary | 551 morphology to function/behaviour is often a very subtle one, requiring ever more sophisticated methods for differentiating products and their benefits for the consumer.Metabolomics is most commonly applied to body/tissue fluids; however, recently the concept of metabolomic analysis of hair was successfully introduced by Sulek et al9 to predict foetal growthrestriction (FGR) by examination of maternal hair samples, and they found a distinct metabolite profile that distinguished FGR from normal pregnancy upon statistical comparison.…”