Related Experiment Video
Updated: Dec 9, 2025
09:37
Navigating MARRVEL, a Web-Based Tool that Integrates Human Genomics and Model Organism Genetics Information
Published on: August 15, 2019
10.2K
Pleiotropic ZIP8 A391T implicates abnormal manganese homeostasis in complex human disease
Laxmi Sunuwar1, Azra Frkatović2, Sodbo Sharapov3
1Department of Medicine, Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
JCI Insight
|September 8, 2020
Summary
A common ZIP8 gene variant (A391T) impacts manganese (Mn) levels and disease risk. This study generated a mouse model showing altered Mn homeostasis and increased susceptibility to colitis, linking Mn to complex human diseases.
Area of Science:
- Genetics
- Biochemistry
- Physiology
Background:
- The ZIP8 gene is a metal transporter crucial for manganese (Mn) homeostasis.
- A common genetic variant, rs13107325 (A391T), in ZIP8 is associated with multiple diseases and reduced blood Mn.
- This variant is among the top pleiotropic single nucleotide polymorphisms (SNPs) identified in genome-wide association studies (GWAS).
Purpose of the Study:
- To create and characterize a mouse model for the ZIP8 A391T genetic variant.
- To investigate the in vivo effects of the ZIP8 A391T variant on Mn homeostasis and disease susceptibility.
- To explore the link between the ZIP8 A391T variant, Mn homeostasis, and glycophenotypes.
Main Methods:
- CRISPR/Cas9-mediated knockin (KI) was used to generate Zip8 393T-KI mice modeling the A391T variant.
- Blood and tissue Mn levels were measured in the KI mice.
- The susceptibility of KI mice to chemically induced colitis was assessed.
- Plasma N-glycan species were analyzed in human cohorts with and without Crohn's disease.
Main Results:
- Zip8 393T-KI mice exhibited reduced blood Mn levels, mirroring the SNP association.
- Abnormal Mn homeostasis was observed in tissues, with decreased Mn in the liver and kidney and increased Mn in bile, indicating hypomorphic ZIP8 function.
- Male Zip8 393T-KI mice showed increased susceptibility to chemically induced colitis.
- The A391T variant was associated with reduced triantennary plasma N-glycan species, a glycophenotype observed in patients with Crohn's disease.
Conclusions:
- The ZIP8 A391T variant impairs Mn homeostasis, leading to altered tissue Mn distribution and increased susceptibility to inflammatory conditions like colitis.
- A genotype-specific glycophenotype linked to Mn-dependent glycosyltransferase activity is associated with the ZIP8 A391T variant.
- These findings highlight the underappreciated role of Mn homeostasis in complex human diseases and suggest potential therapeutic targets.
Related Concept Videos
01:33Pleiotropy
42.7K
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,...
42.7K
02:41Lethal Alleles
17.4K
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...
17.4K
01:43Incomplete Dominance
29.2K
Gregor Mendel's work (1822 - 1884) was primarily focused on pea plants. Through his initial experiments, he determined that every gene in a diploid cell has two variants called alleles inherited from each parent. He suggested that amongst these two alleles, one allele is dominant in character and the other recessive. The combination of alleles determines the phenotype of a gene in an organism.
29.2K
01:31Translation
154.2K
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...
154.2K
01:31Translation
17.2K
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 Life
Proteins are...
Translation Produces the Building Blocks of Life
Proteins are...
17.2K
01:28Human Genetics
1.2K
Human genetics provides a profound framework for understanding the interplay between genetic predispositions and human psychology. At the heart of this discipline lies the study of how genes influence physical traits, behaviors, and susceptibility to diseases. Each person carries a unique genetic code that subtly or significantly shapes their psychological and behavioral landscape.
The complex relationship between genetics and psychology is observable through common biological components such...
The complex relationship between genetics and psychology is observable through common biological components such...
1.2K