Dissertation
Uncovering the genetic contributions to the loose anagen hair phenotype
University of Iowa
Doctor of Philosophy (PhD), University of Iowa
Spring 2025
DOI: 10.25820/etd.007913
Abstract
Hair serves as a critical element of individual identity, playing a significant role in cultural, social, and sexual communication. Conditions affecting hair appearance, including hair loss, can profoundly impact self-esteem and psychological well-being. Loose Anagen Hair Syndrome is a rare, non-scarring form of childhood alopecia characterized by weakly anchored anagen-phase hairs that are easily and painlessly plucked. Affected individuals present with symptoms such as increased hair shedding, sparse hair, and infrequent haircuts. Despite reports suggesting that loose anagen hair syndrome incidence is two per million, underreporting may contribute to this underestimate. While some cases improve with puberty, this improvement may be influenced by changes in personal grooming rather than biological development. Currently, effective treatment is not consistently successful.
Loose anagen hair syndrome presents with notable phenotypic heterogeneity, even among affected members of the same family. Pedigree analysis suggests an autosomal dominant inheritance pattern, though additional inheritance mechanisms may be involved. Previous studies implicated KRT75 variants in loose anagen hair syndrome, identifying disruptions in hair follicle architecture; however, inconsistent segregation of the variant with the phenotype and the lack of replication of this finding necessitates further investigation. Additionally, loose anagen hair syndrome has been observed in individuals with Noonan-like syndrome with loose anagen hair, linking the disorder to RAS/MAPK pathway dysregulation and broader ectodermal anomalies.
This study aims to identify and characterize pathogenic variants associated with loose anagen hair syndrome using genetic and functional approaches. Genome sequencing was conducted on affected individuals and their participating family members, allowing for variant identification and segregation analysis. Stringent variant filtering criteria and in silico pathogenicity prediction tools were applied to prioritize candidate genes. Variants in seven genes (KRT32, ESR2, LPAR6, KRT71, LSS, TRPS1, and TNFRSF13C) were identified in nine families, supporting the notion of genetic heterogeneity in loose anagen hair syndrome.
From the list of identified genes, we focused on KRT32, a gene not associated with hair disorders, to investigate its role in hair anchorage. The p.T99I variant identified in KRT32 was hypothesized to disrupt keratin interactions, weakening anagen hair anchorage. Functional assays were performed to assess the impact of this variant on protein-protein interactions and cellular morphology. A far-western blot assay revealed reduced binding affinity between KRT32 and its co-expressed partner, KRT82. Additionally, in silico intermediate filament network segmentation analysis of high-resolution fluorescence microscopy images demonstrated a reduction in the number and thickness of filaments in keratinocytes expressing the mutant protein.
This study provides compelling evidence for the genetic complexity of loose anagen hair syndrome and identifies novel pathogenic variants contributing to disease pathophysiology. The findings highlight KRT32’s role in hair follicle anchorage and suggest that disruptions in keratin networks contribute to its pathology. Further research is needed to elucidate the broader implications of these variants and explore potential therapeutic targets for affected individuals.
Details
- Title: Subtitle
- Uncovering the genetic contributions to the loose anagen hair phenotype
- Creators
- Marcelo Miranda Melo
- Contributors
- Hatem El-Shanti (Advisor)Alexander Bassuk (Committee Member)Benjamin Darbro (Committee Member)Polly Ferguson (Committee Member)Kelly Messingham (Committee Member)Mary Wilson (Committee Member)
- Resource Type
- Dissertation
- Degree Awarded
- Doctor of Philosophy (PhD), University of Iowa
- Degree in
- Genetics
- Date degree season
- Spring 2025
- DOI
- 10.25820/etd.007913
- Publisher
- University of Iowa
- Number of pages
- xi, 96 pages
- Copyright
- Copyright 2025 Marcelo Miranda Melo
- Language
- English
- Date submitted
- 04/27/2025
- Description illustrations
- Illustrations, tables, graphs, charts
- Description bibliographic
- Includes bibliographical references (pages 63-68).
- Public Abstract (ETD)
Hair is an essential part of one’s identity, influencing self-expression and confidence. Hair loss, as well as, other related conditions can significantly impact self-esteem and mental well-being, especially in children. One such condition, loose anagen hair syndrome, is a rare disorder where hair is poorly anchored in the follicle, making it easy to pull. Typically appearing in childhood, loose anagen hair syndrome causes hair to be sparse, dry, and difficult to manage. Though some cases improve over time, this is not always consistent and can be carried over into adulthood. Current treatment for this disorder is not very successful.
The genetic basis for loose anagen hair syndrome is complex, and the severity of the disorder is very variable among affected individuals, even in the same family. Our research sought to better understand the genetics of loose anagen hair syndrome by analyzing DNA from individuals with the condition and their families and by deeply studying the variations we see. We identified changes in seven genes that may be contributing to the disorder.
We studied a specific genetic variant in a human keratin gene (KRT32) identified in a 3-generation family affected by loose anagen hair syndrome. We suspected that this variant may be responsible for the poor anchoring of the hair shaft during its growth phase. The experimental work showed that this variant alters the anatomy of the hair cells and disrupts interactions between key hair proteins, which we expect makes hair more prone to be painlessly and effortlessly pulled out. These findings enhance our understanding of loose anagen hair syndrome and the important role played by the hair keratins in maintaining a firm anchoring of the hairs.
- Academic Unit
- Interdisciplinary Graduate Program in Genetics
- Record Identifier
- 9984831230102771
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