Centriolar protein PIBF1 is required for craniofacial and forebrain development.

Area of Science:

• Genetics and Developmental Biology
• Cell Biology
• Medical Genetics

Background:

• Primary cilia are vital for cellular signaling, development, and organ function.
• Ciliopathies, caused by ciliary defects, present diverse and challenging clinical features.
• Novel genetic variants are crucial for understanding ciliopathic pathologies.

Purpose of the Study:

• To identify and characterize novel genetic variants affecting ciliary function.
• To investigate the role of the Pibf1 gene in ciliogenesis and associated disorders.
• To expand the understanding of the phenotypic spectrum of ciliopathies.

Main Methods:

• Forward genetic screen utilizing N-ethyl-N-nitrosourea (ENU) mutagenesis.
• Complementation analysis to identify causative gene variants.
• Molecular analysis of gene expression and signaling pathways (Shh, Fgf8, GLI3).

Main Results:

• A novel Pibf1 variant (Pibf1^m1Bei/Null) was identified, essential for ciliogenesis.
• Embryos with the Pibf1 variant displayed craniofacial anomalies and semilobar holoprosencephaly.
• Aberrant Shh and GLI3 processing, with expanded Fgf8 and Lhx6 expression, were observed.

Conclusions:

• PIBF1 and primary cilia play a critical role in establishing embryonic signaling axes.
• Holoprosencephaly is suggested to be part of the ciliopathic phenotypic spectrum for Joubert syndrome.
• This study expands the known clinical manifestations associated with Pibf1 mutations and ciliopathies.