Compound heterozygous GNPTAB mutations cause mucolipidosis II or III alpha/beta in two Chinese families

Area of Science:

• Genetics
• Molecular Biology
• Rare Diseases

Background:

• Mucolipidosis II and III alpha/beta (ML II/III) are rare, autosomal recessive lysosomal storage disorders.
• ML II presents in infancy with severe phenotypes and childhood fatality, while ML III is milder.
• Mutations in the GNPTAB gene are the known cause of ML II/III.

Purpose of the Study:

• To identify the genetic cause of ML II/III in two undiagnosed families.
• To expand the spectrum of known GNPTAB mutations associated with ML II/III.

Main Methods:

• Recruitment of two families with suspected ML II/III.
• Whole-exome sequencing (WES) to identify causative mutations.
• Filtering WES data for genes involved in lysosomal storage diseases with skeletal manifestations.
• Mutational analysis and co-segregation studies for confirmation.

Main Results:

• Identified compound heterozygous GNPTAB mutations (c.2404C>T, p.Q802* and c.2590dup, p.E864Gfs*4) in a family with ML II.
• Detected GNPTAB mutations (c.1364C>T, p.A455V and c.2715+1G>A) in a family with ML III alpha/beta.
• Confirmed the diagnosis of ML II/III in both families through WES.

Conclusions:

• Whole-exome sequencing successfully identified causative GNPTAB mutations in two families with ML II/III.
• The identified mutations broaden the known spectrum of GNPTAB variants.
• Findings may aid in developing improved genetic diagnostic and counseling strategies for ML II/III patients.