New mutations found in the GNPTG gene were identified as the underlying cause of a familial form of a scleroderma-like disease, according to a study published in the journal Pediatric Rheumatology.
The study, “Next Generation Sequencing identifies mutations in GNPTG gene as a cause of familial form of scleroderma-like disease,” was led by Abdelaziz Sefiani, MD, PhD, director of the department of medical genetics at the Institut National d’Hygiène and professor at the Université Mohammed V in Rabat, Morocco.
Scleroderma is a progressive complex disease that affects several organs. It is still unclear what causes the disease, and some genetic abnormalities have been linked to its development and progression.
With the development of new methodologies to evaluate the genetic code, such as Whole Exome Sequencing (WES), knowledge has been gradually increasing about the contribution of genetics to scleroderma risk.
In this study, researchers reported the case of a young male patient who presented tightening of the skin and restricted joint mobility affecting the fingers, wrist, and toes, which progressed to affect the arms, knees, and hip joints as well as the spinal column.
The patient presented additional clinical features including limping, bone deformities, and demineralization as well as increased systemic inflammation. However, none of these are commonly found among patients with scleroderma.
An evaluation of family history revealed that the patient had a younger brother and sister with similar scleroderma-like clinical disease progression. This finding suggested that their disorder could have a genetic background.
The research team conducted a WES analysis on the three siblings. They found two genetic alterations in the GNPTG gene that resulted in a shorter version of the encoded protein.
The GNPTG gene encodes a subunit of a protein complex structure that is responsible for recruiting enzymes involved in the breakdown of a cell’s biological waste.
GNPTG gene mutations are associated with the development of a medical condition called mucolipidosis III gamma. This condition is characterized by reduced levels of the protein complex, meaning that the “digestive” enzymes will not be recruited and the cell will accumulate toxic molecules inside.
The researchers confirmed that the brothers had reduced activity of these digestive enzymes, the hallmark of mucolipidosis III gamma.
“We describe here a Moroccan family with ML III [mucolipidosis III gamma] mimicking scleroderma,” the researchers wrote.
“Our findings expand the mutation spectrum of the GNPTG gene and extend the knowledge of the phenotype–genotype correlation of Mucolipidosis Type III gamma. This report also highlights the diagnostic utility of Next Generation Sequencing particularly when the clinical presentation did not point to specific genes,” the team concluded.
These findings contribute to better understanding of the underlying mechanisms involved in the development of the clinical manifestations of scleroderma.