Submission Details

The relationship between GLB1 and Mucopolysaccharidosis type IVB (a.k.a. Morquio B disease), an autosomal recessive disorder, was evaluated using the ClinGen Clinical Validity Framework as of April, 2023. GLB1 encodes two proteins by alternative splicing: the hydrolytic enzyme, beta-galactosidase (beta-GAL), and the elastin-binding protein (EBP). β-GAL cleaves β-linked galactose residues from the non-reducing end of glycan moieties found in various glycoconjugates. The primary role of EBP is to chaperone the deposition of elastin fibers in the extracellular matrix. Mucopolysaccharidosis type IVB falls within the spectrum of GLB1-related disorders, but unlike GM1 gangliosidosis, the disease is less severe, with primarily skeletal features, absence of neurological features and accumulation of keratan sulfate.

GLB1 was first reported in relation to autosomal recessive Mucopolysaccharidosis type IVB in 1991 (Oshima et al, PMID: 1928092). At least 10 different missense, and a few nonsense, splice site and frameshift variants have been reported in humans. Evidence supporting this gene-disease relationship includes case-level data and experimental data.

OMIM entities: GM1-gangliosidosis, type I (MIM: 230500); GM1-gangliosidosis, type II (MIM: 230600); GM1-gangliosidosis, type III (MIM: 230650); Mucopolysaccharidosis type IVB (Morquio) (MIM: 253010)

Per criteria outlined by the ClinGen Lumping and Splitting Working Group, multiple disease assertions are made in the literature; while the GM1 gangiosidoses phenotypes fall on a spectrum, there are differences in phenotypic variability and potentially molecular mechanism(s) between the GM1 gangliosidosis and Mucopolysaccharidosis type IVB. Therefore, the two entities have been split into separate curations.

Summary of Case Level Data (12 points):

Variants in this gene have been reported in at least 11 probands in 7 publication (PMID: 16941474, 19091613, 7586649, 1928092, 22371915, 33558080, 21497194). Several variants are reported to be recurrent in affected individuals, with the Trp273Leu the most common and likely a founder variant. More evidence is available in the literature, but the maximum score for genetic evidence was reached.

The mechanism for disease is biallelic loss of function.

Summary of experimental data (6 points):

This gene-disease relationship is supported by in vitro functional studies and model organisms evidence. Reduction in β-GAL activity leads to the accumulation of keratan sulfates (PMID: 34539759). GLB1 interacts with NEU1 and CTSA to form the lysosomal multienzyme complex (PMID: 33980489). A knock-in mouse model with the Trp273Leu variant recapitulates the enzyme deficiency but not the clinical phentypes.

In summary, GLB1 is definitively associated with autosomal recessive Mucopolysaccharidosis type IVB. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the Lysosomal Diseases GCEP on April 28, 2023.