Germline De Novo Mutations in ATP1A1 Cause Renal Hypomagnesemia, Refractory Seizures, and Intellectual Disability

Area of Science:

• Biochemistry
• Genetics
• Nephrology

Background:

• Monogenic disorders of magnesium homeostasis are increasingly identified.
• Cellular and epithelial magnesium transport involves key molecular components.
• Infants with unexplained seizures and hypomagnesemia require genetic investigation.

Purpose of the Study:

• To investigate the genetic basis of severe infantile seizures and hypomagnesemia in three infants.
• To elucidate the molecular mechanisms underlying the observed phenotype related to magnesium homeostasis.
• To determine the role of the Na+, K+-ATPase alpha1 subunit (ATP1A1) in magnesium transport and neuronal function.

Main Methods:

• Whole-exome sequencing and Sanger sequencing were used to identify genetic mutations.
• Functional characterization of mutant ATP1A1 in heterologous expression systems.
• Analysis of cation permeability and membrane potential of mutant Na+, K+-ATPase alpha1 subunits.

Main Results:

• Three infants from non-consanguineous families presented with severe hypomagnesemia, renal magnesium wasting, and intractable seizures.
• Heterozygous de novo mutations in the ATP1A1 gene were identified in all affected infants.
• Mutant Na+, K+-ATPase alpha1 subunits exhibited loss of function and abnormal cation permeability, leading to membrane depolarization.
• These findings suggest a critical role for ATP1A1 in renal magnesium handling and neuronal activity.

Conclusions:

• The Na+, K+-ATPase alpha1 subunit (ATP1A1) is essential for maintaining magnesium homeostasis and neuronal function.
• Mutations in ATP1A1 can lead to severe neurological and metabolic disorders in infancy.
• Understanding ATP1A1's role provides insights into monogenic disorders of ion transport and homeostasis.