MANBA, encoding beta-mannosidase, is a lysosomal gene highly expressed in kidney tubule cells [5]. It is involved in lysosomal function, and the endocytosis and autophagy pathways [5]. Understanding MANBA is crucial as its genetic variants are associated with multiple diseases, highlighting its importance in human health.

In chronic kidney disease (CKD), genetic variants in MANBA are associated with the disease. The expression of MANBA was lower in kidneys of subjects with CKD risk genotype [5]. Also, rare heterozygous loss-of-function coding variants in MANBA led to an increased incidence of renal failure [5]. Manba heterozygous and knockout mice developed more severe kidney fibrosis when subjected to toxic injury, indicating MANBA's role in kidney disease development [5].

In multiple sclerosis, the single nucleotide polymorphism rs7665090 in MANBA was associated with the disease. Lymphocytes from MS patients with the rs7665090*GG genotype had reduced MANBA gene expression, enzymatic activity, and metabolic activation, along with lysosomal dysfunction [2].

In a Korean cohort, 14 single nucleotide polymorphisms (SNPs) in MANBA were associated with CKD, and rs4496586 was related to decreased CKD risk, increased eGFR, and decreased creatinine and uric acid concentrations [1]. Additionally, in Swedish but not Chinese populations, a polymorphic CA repeat in MANBA was related to an increased risk of colorectal cancer [3].

In Han Chinese children, a genetic variant in MANBA was associated with attention deficit hyperactivity disorder (ADHD), and the mutation of rs1054037 potentially upregulated MANBA expression [4].

In conclusion, MANBA plays essential roles in lysosomal function, endocytosis, and autophagy, with its genetic variants being associated with diseases like CKD, multiple sclerosis, colorectal cancer, and ADHD. Mouse models, especially Manba knockout models, have been instrumental in revealing its role in kidney fibrosis and CKD, providing valuable insights into disease mechanisms and potential therapeutic targets for these conditions.

References:

1. Kim, Hye-Rim, Jin, Hyun-Seok, Eom, Yong-Bin. 2021. Association between MANBA Gene Variants and Chronic Kidney Disease in a Korean Population. In Journal of clinical medicine, 10, . doi:10.3390/jcm10112255. https://pubmed.ncbi.nlm.nih.gov/34070965/

2. González-Jiménez, Adela, López-Cotarelo, Pilar, Agudo-Jiménez, Teresa, Urcelay, Elena, Espino-Paisán, Laura. 2022. Impact of Multiple Sclerosis Risk Polymorphism rs7665090 on MANBA Activity, Lysosomal Endocytosis, and Lymphocyte Activation. In International journal of molecular sciences, 23, . doi:10.3390/ijms23158116. https://pubmed.ncbi.nlm.nih.gov/35897697/

3. Gao, Jingfang, Arbman, Gunnar, He, Lujun, Rosell, Johan, Sun, Xiao-Feng. 2007. MANBA polymorphism was related to increased risk of colorectal cancer in Swedish but not in Chinese populations. In Acta oncologica (Stockholm, Sweden), 47, 372-8. doi:. https://pubmed.ncbi.nlm.nih.gov/17899454/

4. Chen, Xinzhen, Yao, Ting, Cai, Jinliang, Fu, Xihang, Wu, Jing. 2022. A novel genetic variant potentially altering the expression of MANBA in the cerebellum associated with attention deficit hyperactivity disorder in Han Chinese children. In The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry, 23, 548-559. doi:10.1080/15622975.2021.2014248. https://pubmed.ncbi.nlm.nih.gov/34870556/

5. Gu, Xiangchen, Yang, Hongliu, Sheng, Xin, Rader, Daniel J, Susztak, Katalin. . Kidney disease genetic risk variants alter lysosomal beta-mannosidase (MANBA) expression and disease severity. In Science translational medicine, 13, . doi:10.1126/scitranslmed.aaz1458. https://pubmed.ncbi.nlm.nih.gov/33441424/