Pathogenic Variants in GPC4 Cause Keipert Syndrome

Area of Science:

• Genetics
• Developmental Biology
• Molecular Biology

Background:

• Glypicans are cell-surface proteoglycans crucial for growth factor signaling and morphogenesis.
• Keipert syndrome (nasodigitoacoustic syndrome) is a rare genetic disorder with distinct craniofacial and digital features.

Purpose of the Study:

• To identify the genetic cause of Keipert syndrome.
• To investigate the functional consequences of identified genetic variants in GPC4.
• To establish GPC4 as a causative gene for Keipert syndrome.

Main Methods:

• Whole-exome sequencing to identify genetic variants in affected families.
• Segregation analysis and X-inactivation studies in carrier females.
• Functional studies of recombinant GPC4 proteins and Gpc4 knockout mouse models.

Main Results:

• Identified hemizygous truncating variants in GPC4 in multiple families with Keipert syndrome.
• Demonstrated that GPC4 variants lead to loss of N-linked glycosylation and GPI anchor sites, reducing protein stability.
• Gpc4 knockout mice exhibited craniofacial and digital abnormalities mirroring Keipert syndrome features.

Conclusions:

• Pathogenic variants in GPC4 cause loss of function, leading to Keipert syndrome.
• GPC4 is the third glypican gene linked to a human genetic syndrome.
• This finding expands our understanding of glypican function in human development and disease.