Mutations in KEOPS-complex genes cause nephrotic syndrome with primary microcephaly

Area of Science:

• Genetics
• Developmental Biology
• Molecular Biology

Background:

• Galloway-Mowat syndrome (GAMOS) is a rare genetic disorder.
• It presents with early-onset nephrotic syndrome and microcephaly with brain anomalies.
• The genetic underpinnings of GAMOS remain largely unknown.

Purpose of the Study:

• To identify the genetic causes of Galloway-Mowat syndrome.
• To investigate the molecular mechanisms underlying GAMOS pathogenesis.
• To establish a link between KEOPS complex function and GAMOS.

Main Methods:

• Whole-exome sequencing to identify causative genes in GAMOS patients.
• CRISPR-Cas9 gene editing in zebrafish and mice models.
• Cellular assays assessing proliferation, protein translation, ER stress, DNA damage, and podocyte function.

Main Results:

• Recessive mutations in OSGEP, TP53RK, TPRKB, and LAGE3 (KEOPS complex subunits) were identified in 37 individuals with GAMOS.
• CRISPR-Cas9 knockout models recapitulated microcephaly and lethality observed in human patients.
• Gene knockdown impaired cell proliferation, protein translation, induced ER stress, DNA damage, apoptosis, and podocyte dysfunction.

Conclusions:

• Four novel monogenic causes of GAMOS involving the KEOPS complex have been identified.
• This study establishes a direct link between KEOPS complex dysfunction and GAMOS.
• The findings elucidate potential pathogenic mechanisms involving protein translation, cellular stress, and cytoskeletal integrity.