AUTHOR=Jin Jie-Yuan , Wu Pan-Feng , Luo Fang-Mei , Guo Bing-Bing , Zeng Lei , Fan Liang-Liang , Tang Ju-Yu , Xiang Rong 

TITLE=GLIS Family Zinc Finger 1 was First Linked With Preaxial Polydactyly I in Humans by Stepwise Genetic Analysis

JOURNAL=Frontiers in Cell and Developmental Biology

VOLUME=9

YEAR=2022

URL=https://www.frontiersin.org/journals/cell-and-developmental-biology/articles/10.3389/fcell.2021.781388

DOI=10.3389/fcell.2021.781388

ISSN=2296-634X

ABSTRACT=<p><bold>Background:</bold> Preaxial polydactyly (PPD) is one of the most common developmental malformations, with a prevalence of 0.8–1.4% in Asians. PPD is divided into four types, PPD I–IV, and PPD I is the most frequent type. Only six loci (<italic>GLI1</italic>, <italic>GLI3</italic>, <italic>STKLD1</italic>, ZRS, pre-ZRS, and a deletion located 240 kb from <italic>SHH</italic>) have been identified in non-syndromic PPD cases. However, pathogenesis of most PPD patients has never been investigated. This study aimed to understand the genetic mechanisms involved in the etiology of PPD I in a family with multiple affected members.</p><p><bold>Methods:</bold> We recruited a PPD I family (PPD001) and used stepwise genetic analysis to determine the genetic etiology. In addition, for functional validation of the identified <italic>GLIS1</italic> variant, <italic>in vitro</italic> studies were conducted. <italic>GLIS1</italic> variants were further screened in additional 155 PPD cases.</p><p><bold>Results:</bold> We identified a <italic>GLIS1</italic> variant (NM_147193: c.1061G &gt; A, p.R354H) in the PPD001 family. <italic>In vitro</italic> studies showed that this variant decreased the nuclear translocation of GLIS1 and resulted in increased cell viability and migration. RNA sequencing revealed abnormal <italic>TBX4</italic> and <italic>SFRP2</italic> expression in 293T cells transfected with mutant GLIS1. Additionally, we identified a <italic>GLIS1</italic> variant (c.664G &gt; A, p.D222N) in another PPD case.</p><p><bold>Conclusion:</bold> We identified two <italic>GLIS1</italic> variants in PPD I patients and first linked <italic>GLIS1</italic> with PPD I. Our findings contributed to future molecular and clinical diagnosis of PPD and deepened our knowledge of this disease.</p>