A novel Bi-Allelic pathogenic MCOLN1 variant underlying mucolipidosis type IV in an Iranian family: clinical, genetic, and molecular dynamics-based structural analysis.

backgroundMucolipidosis type IV (MLIV) is a rare autosomal recessive lysosomal storage disorder due to biallelic pathogenic variants in the MCOLN1 gene. Its main impact is on the central nervous system, leading to severe psychomotor delays, progressive visual impairment, and characteristic brain abnormalities.

methodsA 12-year-old male from a consanguineous Iranian family underwent clinical and imaging evaluations for suspected MLIV. Exome sequencing identified the causative variant, confirmed by Sanger co-segregation analysis, in silico tools assessed pathogenicity, protein stability, and structural impact, followed by 3D modeling (I-TASSER) and protein interaction analysis (STRING). Molecular dynamics simulations were performed with GROMACS 2020.4 employing the GROMOS96 43a1 force field to compare wild-type and mutant structures, evaluating key parameters, including root mean square deviation (RMSD), radius of gyration (Rg), hydrogen bond profiles, and solvent-accessible surface area (SASA), were analyzed, and results which were visualized using GraphPad Prism.

resultsExome sequencing revealed a previously unreported homozygous nonsense variant in MCOLN1 (NM_020533.3: c.1384G > T; p.Glu462). This variant introduces a premature termination codon predicted to yield a truncated protein if translated; however, it is likely subject to nonsense-mediated mRNA decay, leading to transcript degradation and consequent loss of functional protein. Sanger sequencing confirmed the variant and its co-segregation within the family, with both parents heterozygous carriers and the patient homozygous. Bioinformatic analysis classified the variant as likely pathogenic, with high deleteriousness scores. Structural modeling indicated disruption of a helical domain. STRING analysis demonstrated strong functional associations between MCOLN1 and its paralogs MCOLN2 and MCOLN3, supporting its biological relevance. This variant expands the known spectrum of genetic causes of MLIV.

conclusionWe report the first Iranian case of MLIV due to a novel homozygous nonsense variant in MCOLN1 (c.1384G > T; p.Glu462*). These findings expand the spectrum of MLIV, underscore phenotypic variability and the value of population-specific genetic data in rare disease diagnostics, and support the inclusion of this variant in targeted diagnostic panels for Iranian patients.