Hyperinsulinism/hyperammonemia syndrome caused by biallelic SLC25A36 mutation

Area of Science:

• Genetics
• Biochemistry
• Pediatrics

Background:

• Hyperinsulinism/hyperammonemia (HI/HA) syndrome is typically linked to dominant gain-of-function mutations in GLUD1.
• Recent studies suggest biallelic mutations in SLC25A36, encoding pyrimidine nucleotide carrier 2 (PNC2), can also cause HI/HA.
• PNC2 transports nucleotides across the inner mitochondrial membrane, and its dysfunction may affect glutamate dehydrogenase activity.

Purpose of the Study:

• To investigate the role of SLC25A36 mutations in HI/HA syndrome.
• To confirm the disease-causing potential of a specific SLC25A36 splice-site mutation.
• To delineate the clinical phenotype associated with biallelic SLC25A36 mutations.

Main Methods:

• Combined linkage analysis and exome sequencing in Bedouin Israeli families.
• Analysis of SLC25A36 mRNA and protein expression in patient blood and fibroblasts.
• Clinical evaluation of affected individuals.

Main Results:

• Identified a homozygous splice-site mutation (c.284+3A>T) in SLC25A36 in four individuals from two families.
• The mutation caused exon 3 skipping but did not abolish SLC25A36 mRNA or protein expression.
• Affected individuals presented with hyperinsulinism, hyperammonemia, borderline low birth weight, and seizures, but normal intellect and no other significant morbidities.

Conclusions:

• Biallelic SLC25A36 mutations are a confirmed cause of HI/HA syndrome.
• The identified mutation leads to a specific clinical phenotype, differentiating it from previously described cases.
• This study expands the genetic basis of HI/HA syndrome and clarifies its clinical presentation.