KLHL4, a member of the KLHL protein family, is located on the X chromosome. It binds the Cul3 E3 ligase, potentially mediating ubiquitination of interacting proteins. KLHL4 is associated with X-linked cleft palate (CPX) disorder and may play roles in cell-cycle regulation and ectodermal differentiation [1,3,4]. It has been identified as a potential biomarker in multiple diseases, highlighting its overall biological importance [2,5,6,7,8].

Studies on Klhl4-knocked-out MEF mouse embryonic fibroblasts showed that they proliferated faster than WT MEF cells, suggesting that KLHL4 may inhibit cell proliferation. KLHL4 can activate transcription of p21WAF/CDKN1A, a major negative regulator of the cell-cycle, and interact with p53 to enhance its binding to the p21WAF/CDKN1A gene's response element [1]. Biochemically, in vertebrate head development, CRL3-KLHL4 restricts signaling of the cytoskeletal regulator CDC42, and loss of CRL3-KLHL4 or a disease-associated KLHL4 variant leads to defective ectodermal patterning and neurulation [3].

In conclusion, KLHL4 is crucial for regulating cell proliferation and ectodermal development. Gene-knockout models, like the Klhl4-knocked-out MEF cells, have been instrumental in revealing its role in cell-cycle regulation. These findings contribute to understanding diseases such as X-linked cleft palate and potentially other conditions where KLHL4 is implicated as a biomarker [1,3,4].