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

Area of Science:

• Genetics
• Developmental Biology
• Molecular Medicine

Background:

• Preaxial polydactyly (PPD) is a common congenital limb malformation, with PPD I being the most frequent subtype.
• Genetic underpinnings of PPD, particularly PPD I, remain largely unexplored, with only a few loci identified previously.
• Understanding the genetic basis is crucial for diagnosis and potential therapeutic strategies.

Purpose of the Study:

• To investigate the genetic mechanisms underlying preaxial polydactyly type I in a multiplex family.
• To identify novel genetic variants associated with PPD I.
• To functionally characterize the identified variants in vitro.

Main Methods:

• Stepwise genetic analysis was performed on a PPD I family (PPD001).
• In vitro functional studies were conducted to validate the effects of identified GLIS1 variants.
• GLIS1 variants were screened in an additional cohort of 155 PPD cases.

Main Results:

• A novel GLIS1 variant (c.1061G > A, p.R354H) was identified in the PPD001 family.
• The identified GLIS1 variant impaired nuclear translocation, enhancing cell viability and migration.
• Abnormal expression of TBX4 and SFRP2 was observed in cells with mutant GLIS1.
• A second GLIS1 variant (c.664G > A, p.D222N) was found in another PPD case.

Conclusions:

• This study establishes GLIS1 as a novel gene associated with preaxial polydactyly type I.
• Two distinct GLIS1 variants were identified in PPD I patients.
• Findings advance the molecular and clinical diagnosis of PPD and deepen understanding of its pathogenesis.