Related Experiment Video
Updated: Feb 19, 2026
08:04
Identification and Classification of Position-specific GABAA Receptor Subunit Missense Variants for Their Role In Hippocampal Pyramidal Neurons
Published on: June 6, 2025
1.6K
Mutations in GPAA1, Encoding a GPI Transamidase Complex Protein, Cause Developmental Delay, Epilepsy, Cerebellar
Thi Tuyet Mai Nguyen1, Yoshiko Murakami2, Eamonn Sheridan3
1Centre Hospitalier Universitaire Sainte Justine Research Center, University of Montreal, Montreal, QC H3T1C5, Canada.
American Journal of Human Genetics
|November 4, 2017
Summary
Mutations in GPAA1, essential for glycosylphosphatidylinositol (GPI) anchor attachment, cause developmental disorders. This study identifies GPAA1 mutations linked to neurological and skeletal abnormalities, highlighting the transamidase complex
Area of Science:
- Genetics and Molecular Biology
- Cell Biology
- Neuroscience
Background:
- Glycosylphosphatidylinositol (GPI) anchors attach about 1 in 200 mammalian proteins to the cell membrane, crucial for neurological functions.
- The transamidase complex, including GPAA1, attaches GPI anchors to proteins in the endoplasmic reticulum.
Purpose of the Study:
- To investigate the role of GPAA1 in human health by identifying mutations and their associated phenotypes.
- To understand the functional consequences of GPAA1 mutations on GPI-anchored protein biogenesis and cellular function.
Main Methods:
- Whole-exome sequencing to identify GPAA1 mutations in affected individuals.
- Analysis of GPAA1 mRNA levels and cell-surface expression of GPI-anchored proteins using flow cytometry.
- Functional rescue experiments in patient-derived fibroblasts.
Main Results:
- Bi-allelic mutations in GPAA1 were identified in ten individuals from five families, including frameshift, splicing, and missense mutations.
- Affected individuals presented with global developmental delay, hypotonia, seizures, cerebellar atrophy, and osteopenia.
- Mutations led to decreased GPAA1 mRNA and reduced cell-surface levels of GPI-anchored proteins, partially rescued by wild-type GPAA1 expression.
Conclusions:
- GPAA1 is essential for normal neurological and skeletal development.
- Defects in the GPI transamidase complex can lead to severe developmental disorders.
- Targeting the transamidase complex may offer therapeutic avenues for related genetic disorders.
More Related Videos
08:22A Novel Strategy Combining Array-CGH, Whole-exome Sequencing and In Utero Electroporation in Rodents to Identify Causative Genes for Brain Malformations
Published on: December 1, 2017
9.2K
09:34Targeted Next-generation Sequencing and Bioinformatics Pipeline to Evaluate Genetic Determinants of Constitutional Disease
Published on: April 4, 2018
34.9K
Related Concept Videos
01:20Inborn Errors of Metabolism
932
Phenylketonuria (PKU) is a protein metabolism disorder characterized by high blood levels of the amino acid phenylalanine. This results from a mutation in the gene responsible for phenylalanine hydroxylase, an enzyme that converts phenylalanine into tyrosine. When this enzyme is deficient, phenylalanine builds up in the blood, leading to symptoms such as vomiting, rashes, seizures, growth deficiency, and severe mental retardation. An early diagnosis and a diet restricting phenylalanine intake...
932
02:30Genomic Imprinting and Inheritance
37.4K
Diploid organisms inherit genetic material through chromosomes from both parents. Copies of the same gene are known as alleles. In most cases, both alleles are simultaneously expressed and allow various cellular processes to function optimally. If one of the alleles is missing or mutated, the expression of the other allele can compensate; however, this is not true for all genes.
The expression of some genes depends on which parent passed the gene to the offspring, through a phenomenon known as...
The expression of some genes depends on which parent passed the gene to the offspring, through a phenomenon known as...
37.4K
01:33Pleiotropy
43.5K
Pleiotropy is the phenomenon in which a single gene impacts multiple, seemingly unrelated phenotypic traits. For example, defects in the SOX10 gene cause Waardenburg Syndrome Type 4, or WS4, which can cause defects in pigmentation, hearing impairments, and an absence of intestinal contractions necessary for elimination. This diversity of phenotypes results from the expression pattern of SOX10 in early embryonic and fetal development. SOX10 is found in neural crest cells that form melanocytes,...
43.5K
02:41Lethal Alleles
18.4K
Agouti: A Lethal Allele
Lucien Cuénot discovered lethal alleles in 1905 while studying the inheritance of coat color in mice. The agouti gene is responsible for the color of the coat in mice. This gene codes for an agouti-signaling protein, which is responsible for melanin distribution in mammals. The wild-type allele gives rise to gray-brown coat color in mice, while the mutant allele gives rise to yellow coat color. In addition to coat color, the agouti gene is associated with the yellow...
Lucien Cuénot discovered lethal alleles in 1905 while studying the inheritance of coat color in mice. The agouti gene is responsible for the color of the coat in mice. This gene codes for an agouti-signaling protein, which is responsible for melanin distribution in mammals. The wild-type allele gives rise to gray-brown coat color in mice, while the mutant allele gives rise to yellow coat color. In addition to coat color, the agouti gene is associated with the yellow...
18.4K
01:22Activation and Inactivation of G Proteins
11.8K
Heterotrimeric G proteins are guanine nucleotide-binding proteins. As the name suggests, heterotrimeric G proteins are composed of three subunits: alpha, beta, and gamma. They remain GDP-bound or GTP-bound inside the cells and switch between inactive/active states. The Gα subunit possesses the nucleotide-binding pocket that binds guanine nucleotides and switches between GDP or GTP-bound states. In contrast, the Gꞵ and Gγ subunits are always bound together with high...
11.8K
01:31Translation
157.6K
Lesson: Translation
Translation is the process of synthesizing proteins from the genetic information carried by messenger RNA (mRNA). Following transcription, it constitutes the final step in the expression of genes. This process is carried out by ribosomes, complexes of protein and specialized RNA molecules. Ribosomes, transfer RNA (tRNA), and other proteins produce a chain of amino acids—the polypeptide—as the end product of translation.
Translation Produces the Building Blocks of...
Translation is the process of synthesizing proteins from the genetic information carried by messenger RNA (mRNA). Following transcription, it constitutes the final step in the expression of genes. This process is carried out by ribosomes, complexes of protein and specialized RNA molecules. Ribosomes, transfer RNA (tRNA), and other proteins produce a chain of amino acids—the polypeptide—as the end product of translation.
Translation Produces the Building Blocks of...
157.6K