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EPS8L3 has been investigated as a candidate gene for Marie Unna hereditary hypotrichosis (MUHH), an autosomal dominant disorder characterized by coarse, wiry, and twisted hair early in life followed by progressive hair loss. Initial genetic studies identified a missense mutation in this gene that cosegregated with the disease phenotype in a four‐generation family. This observation provided early support for its potential role in MUHH (PMID:23099647).
Genetic evidence from a case report demonstrated the presence of the EPS8L3 mutation in all eight affected family members while it was absent in seven unaffected individuals. Additionally, the mutation was not detected in 676 unrelated healthy controls, reinforcing the notion that this alteration may be disease‐causative. The reported segregation data contributed significantly to the genetic evidence, albeit from a single family cohort (PMID:23099647).
The specific variant reported is c.22G>A (p.Ala8Thr). In preparing this HGVS-compliant description, extraneous transcript or gene symbol details were removed so as to provide clarity and consistency in reporting. This variant represents the complete coding change with both a c. DNA-level alteration and the corresponding protein change using three-letter amino acid codes, as required for rigorous variant documentation.
Functional assessments, although not extensive at this time, have provided preliminary insight into the potential impact of EPS8L3 on hair follicle biology. Such studies suggest that the mutation could disrupt normal protein function, thereby impairing hair follicle development or maintenance. However, detailed mechanistic studies remain sparse, limiting the overall strength of functional evidence (PMID:23099647).
The association between EPS8L3 and MUHH is further complicated by subsequent multi-patient studies. In an independent analysis focusing on multiple candidate genes, no pathogenic variants in EPS8L3 were detected in MUHH patients; instead, mutations in HR were identified as causative. This conflicting observation raises concerns about the reproducibility of the EPS8L3 findings, resulting in an overall disputed association (PMID:30809827).
In conclusion, while initial family-based evidence provided moderate genetic support through clear segregation of the EPS8L3 c.22G>A (p.Ala8Thr) variant with MUHH, subsequent studies have not corroborated these findings. The discrepancy between the datasets necessitates further independent investigations. Key take‑home: The current evidence, though suggestive, disputes the association of EPS8L3 with MUHH, and additional studies are essential for definitive clinical utility.
Gene–Disease AssociationDisputedA case report demonstrated cosegregation of the EPS8L3 c.22G>A (p.Ala8Thr) variant in a four‐generation MUHH family with eight affected individuals and seven unaffected, supporting a potential role (PMID:23099647). However, an independent multi-patient study failed to detect pathogenic variants in EPS8L3 in MUHH patients, instead implicating HR (PMID:30809827), leading to a disputed overall association. Genetic EvidenceModerateThe initial report provided robust segregation data with the mutation being present in eight affected individuals and absent in both seven unaffected family members and 676 healthy controls (PMID:23099647). Functional EvidenceLimitedPreliminary functional assessments indicate a potential impact of the EPS8L3 mutation on hair follicle biology, but detailed mechanistic studies remain sparse. |