# A biallelic variant in GORASP1 causes a novel Golgipathy with glycosylation and mitotic defects

## TL;DR

A genetic variant in GORASP1 causes a new Golgi-related disorder with issues in glycosylation and cell division.

## Contribution

The first human pathogenic variant in GORASP1 is identified and linked to a novel Golgipathy.

## Key findings

- The GORASP1 variant leads to complete absence of GRASP65 protein.
- Loss of GRASP65 causes glycosylation defects and mitotic delays in human cells.
- CRISPR/Cas9 modeling confirmed the variant's effects in RPE cells.

## Abstract

This study identifies the first human pathogenic variant in GORASP1, the gene encoding the Golgi stacking protein GRASP65, and demonstrates its consequences on glycosylation and mitotic progression.

GRASP65 is a Golgi-associated peripheral protein encoded by the GORASP1 gene and required for Golgi cisternal stacking in vitro. A key role of GRASP65 in the regulation of cell division has also been suggested. However, depletion of GRASP65 in mice has little effect on the Golgi structure and the gene has not been associated with any human phenotype to date. Here, we report the identification of the first human pathogenic variant of GORASP1 (c.1170_1171del; p.Asp390Glufs*18) in a patient combining a neurodevelopmental disorder with neurosensory, neuromuscular, and skeletal abnormalities. Functional analysis revealed that the variant leads to a total absence of GRASP65. The structure of the Golgi apparatus did not show fragmentation, but glycosylation anomalies such as hyposialylation were detected. Mitosis analyses revealed an excess of prometaphases and metaphases with polar chromosomes, suggesting a delay in the cell cycle. These phenotypes were recapitulated in RPE cells in which a similar mutation was introduced by CRISPR/Cas9. These results indicate that loss of GRASP65 in humans causes a novel Golgipathy associated with defects in glycosylation and mitotic progression.