Researchers Identify Two Mutations Potentially Linked to Rare Blood Disorder


The mutations, C594Y and P735R, were found in the GNE gene and may influence sialylation, a process that is crucial for brain development.

Blood test with sample -- Image credit: shidlovski |

Image credit: shidlovski |

Findings published in Blood Advances indicate there are 2 novel gene mutations that may be responsible for a rare blood disorder. The mutations, which were found on the GNE gene and impact an enzyme of the same name, was determined to be involved in the synthesis of sialic acid which has a significant role in brain development. According to the authors, the mutations were first discovered in a pediatric patient with macrothrombocytopenia, or giant platelet disorder.1

“We identified 2 novel mutations—C594Y and P735R—in the GNE gene, which is required for sialic acid biosynthesis. By making mice carrying P735R of patient-derived mutations, we set out to determine if GNE mutations cause macrothrombocytopenia. This is the first study confirming that GNE mutations cause platelet problems in mice,” said co-first author Yuji Kondo, PhD, lecturer at the Institute for Glyco-core Research at Nagoya University, Nagoya, Japan, in a press release.1

The study reports on a pediatric patient with severe macrothrombocytopenia, and the researchers used next-generation sequencing technology to identify compound heterozygous GNE variants in the patient. Further, the authors investigated the pathological significance of the variants by using a new mouse model which had a homozygous P735R mutation. Following the in vivo segment, patient-derived variants were analyzed by establishing a GNE-knockout mouse endothelial line.2

When the researchers identified the mutations, replications were made of the P735R mutation, because it was believed this particular mutation would be more likely to alter GNE. Previous researcher showed that mice given other GNE mutations survived after birth; however, the current study showed that the mice that were given the P735R mutation died as embryos because of fatal brain bleeds. This finding shows the role of the GNE enzyme and sialylation in angiogenesis during embryonic brain development. The authors note that this is still valuable information, as it provided them with answers and questions that can be explored in future research.1,2

“Our body has 2 pathways for sialic acid synthesis. One is a GNE-mediated ‘de novo’ sialic acid biosynthetic pathway. The other is a ‘salvage’ pathway from lysosomal degradation of glycoconjugates. Our study indicates that the GNE-mediated de novo sialic acid biosynthetic pathway is critical for embryonic development, and the salvage pathway and supply of sialic acid from the pregnant mother through the placenta to the fetus are not sufficient for development,” said Kondo in the press release.1

Further, the study authors believe that the mice with the other mutation, C594Y, will live longer. They note that this hypothesis can provide additional opportunities of studying the genetic mutations as well as how they may influence blood disorders.1

“Our next step is to analyze phenotypes of C594Y-carrying mice to see if they have the platelet problem. If so, we will analyze the mechanism underlying macrothrombocytopenia, and find approaches for therapeutic intervention. We will also seek to learn more about the myopathy phenotype and identify the molecular mechanism for how GNE myopathy develops and what factors contribute to fine-tuned myopathy development,” said Kondo in the press release.1

1. Institute for Glyco-Core Research (IGCORE), Tokai National Higher Education and Research System. Two new mutations identified as possible causes of rare blood disorder. News release. March 26, 2024. Accessed March 29, 2024.
2. Huang, L, Kondo, Y, Cao, L, et al. Novel GNE missense variants impair de novo sialylation and cause defective angiogenesis in the developing brain in mice. Blood Adv 2024; 8 (4): 991–1001. doi:10.1182/bloodadvances.2023011490
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