# Association of certain biochemical parameters related to bone cycle with genotype in MPS IIIB patients

## TL;DR

This study explores how genetic variations in MPS IIIB patients relate to bone-related biochemical markers and identifies new mutations that may affect enzyme activity.

## Contribution

The study identifies a novel NAGLU gene mutation (p.Trp103Cys) and suggests reclassifying a previously benign variation as pathogenic.

## Key findings

- MPS IIIB patients showed significantly higher levels of MMP2, MMP9, TIMP1, and TIMP2, and lower cathepsin K compared to controls.
- Only two patients had previously defined pathogenic NAGLU gene alterations, while others had variations with potential protein-modifying effects.
- The novel mutation p.Trp103Cys was found to be damaging based on SIFT and PolyPhen analyses.

## Abstract

The aims of this study are to investigate the genotype–phenotype correlation in Sanfilippo type B (MPS IIIB) patients in terms of bone formation/resorption parameters and to determine the release/inhibition of biomarkers accompanying osteoporosis.

Plasma levels of osteoprotegerin (OPG), matrix metalloproteinases (MMP2 and MMP9), tissue inhibitors of metalloproteinase (TIMP1 and TIMP2) and cathepsin K were examined using the ELISA method for a MPS IIIB patient group and a control group. At the same time, mutations in the NAGLU gene causing the disease were identified by whole exome sequencing, and their correlation with biochemical parameters was investigated.

The enzyme analysis results showed that MMP2, MMP9, TIMP1, and TIMP2 were significantly high in the study group, while cathepsin K was low. OPG levels were similar between the two groups. The genetic analysis of patients with MPS IIIB was performed by sequencing all exons and exon–intron junction regions of the NAGLU gene using a next-generation sequencing (NGS) system. In this way, variations were detected qualitatively with high read depths. The analyses found that only two patients had a previously pathogenically defined alteration. In addition, the impact assessment analyses detected alterations with a modifying effect on protein structure.

The genetic analysis results indicate the need to consider a variation classified as benign in the OMIM database as pathogenic because the variations found in the patients (p.Arg737Gly and p.Trp103Cys) have somehow altered enzyme activity. The mutation p.Trp103Cys, a novel NAGLU gene mutation in the first exon, was detected in one patient; additionally, SIFT and PolyPhen analyses confirmed it as damaging. Further functional analyses of this variation should be conducted to gather more comprehensive information.