GALNS, also known as N-acetylgalactosamine-6-sulfatase, is essential for the breakdown of glycosaminoglycans such as keratan sulfate and chondroitin 6-sulfate. Deficiency in GALNS activity due to gene mutations leads to mucopolysaccharidosis IVA (MPS IVA, Morquio A syndrome), an autosomal recessive lysosomal storage disorder [1,2,3,4,5,6,7].

Mutations in the GALNS gene are diverse, including missense, nonsense, splicing, small frameshift deletions/insertions, intronic, and large del/ins and complex rearrangements. Different variants result in different levels of residual GALNS activity, leading to a wide range of clinical manifestations in MPS IVA patients. For example, most patients with at least one GALNS null variant are classified as having a severe phenotype, while missense variants mapped to different residues of the GALNS protein can lead to different phenotypes [1,3].

In conclusion, GALNS is crucial for the proper degradation of specific glycosaminoglycans. Understanding GALNS through the study of its mutations in the context of MPS IVA helps in correct molecular diagnoses, genetic counseling, and disease management. Research on GALNS gene variants contributes to a better understanding of the molecular basis of MPS IVA and provides insights into potential genotype-phenotype correlations [1,4].

References:

1. Zanetti, Alessandra, D'Avanzo, Francesca, AlSayed, Moeenaldeen, Morrone, Amelia, Tomanin, Rosella. 2021. Molecular basis of mucopolysaccharidosis IVA (Morquio A syndrome): A review and classification of GALNS gene variants and reporting of 68 novel variants. In Human mutation, 42, 1384-1398. doi:10.1002/humu.24270. https://pubmed.ncbi.nlm.nih.gov/34387910/

2. Morrone, A, Tylee, K L, Al-Sayed, M, Wang, R Y, Miller, N. 2014. Molecular testing of 163 patients with Morquio A (Mucopolysaccharidosis IVA) identifies 39 novel GALNS mutations. In Molecular genetics and metabolism, 112, 160-70. doi:10.1016/j.ymgme.2014.03.004. https://pubmed.ncbi.nlm.nih.gov/24726177/

3. Yi, Mengni, Wang, Yu, Gao, Xiaolan, Maegawa, Gustavo H B, Zhang, Huiwen. 2022. Investigation of GALNS variants and genotype-phenotype correlations in a large cohort of patients with mucopolysaccharidosis type IVA. In Journal of inherited metabolic disease, 45, 593-604. doi:10.1002/jimd.12491. https://pubmed.ncbi.nlm.nih.gov/35212421/

4. Morrone, Amelia, Caciotti, Anna, Atwood, Robert, Zawadzki, Karl A, Miller, Nicole. 2014. Morquio A syndrome-associated mutations: a review of alterations in the GALNS gene and a new locus-specific database. In Human mutation, 35, 1271-9. doi:10.1002/humu.22635. https://pubmed.ncbi.nlm.nih.gov/25137622/

5. Sawamoto, Kazuki, Álvarez González, José Víctor, Piechnik, Matthew, Suzuki, Yasuyuki, Tomatsu, Shunji. 2020. Mucopolysaccharidosis IVA: Diagnosis, Treatment, and Management. In International journal of molecular sciences, 21, . doi:10.3390/ijms21041517. https://pubmed.ncbi.nlm.nih.gov/32102177/

6. Haddley, K. . Elosulfase alfa. In Drugs of today (Barcelona, Spain : 1998), 50, 475-83. doi:10.1358/dot.2014.50.7.2177904. https://pubmed.ncbi.nlm.nih.gov/25101330/

7. Sheth, Harsh, Naik, Premal, Shah, Maulin, Sheth, Frenny, Sheth, Jayesh. 2022. The GALNS p.P77R variant is a probable Gujarati-Indian founder mutation causing Mucopolysaccharidosis IVA syndrome. In BMC genomics, 23, 458. doi:10.1186/s12864-022-08693-4. https://pubmed.ncbi.nlm.nih.gov/35729508/