Cause of MSUD

MSUD is caused by a mutation that results in a deficiency for one or more of the 6 subunits that make up BCKD complex (branched-chain alpha-keto-acid dehydrogenase). This creates a dysfunctional BCKD complex which is ineffective in breaking down the branched-chain amino acids in our body. (Leucine, Isoleucine and Valine).

WHAT IS THE BCKD complex? 

Branched-chain keto acid dehydrogenase (BCKD) is a multienzyme complex found in the inner membrane of mitochondria and is crucial in the metabolism of Leucine, isoleucine and valine amino acids. 




The complex consists of 6 subunits: branched-chain alpha-keto acid decarboxylase (E1) which is made up of 2 alpha subunits and 2 beta subunits, Dihydrolipoamide branched-chain transacylase (E2) and dihydrolipoamide dehydrogenase (E3).

The phosphorylation status of the E1a subunit affects the regulation of enzyme activity. BCKDC kinase (BDK) inactivates BCKDC and mitochondrial matrix resident type 2C phosphatase (PP2Cm) activates it.

Mutations

The most common mutations occur in the E1 complex.  




One example of a common mutation in the E1 complex is the mutation in the BCKDHA gene which encodes for the Alpha subunit of the complex.

The E1 complex is made up of 2 alpha subunits (from the gene BCKDHA) and 2 beta subunits. (from BCKDHB).

We will first cover the mutation of the BCKDHA gene, then the mutation of the BCKDHB gene.

BCKDHA:  The official name of the BCKDHA gene is the Branched chain keto acid dehydrogenase E1, alpha polypeptide.

BCKDHA gene is located from base pair 41,903,693 to base pair 41,930,909 on chromosome 19.




Most BCKDHA mutations change the single amino acids in the alpha subunit of the E1 complex.

The MOST COMMON amino acid mutation replaces the Tyrosine with Asparagine at position 438.

*note: The gene name is BCKDHA

This mutation disrupts the functionality of the BCKD complex and prevents it from breaking down the branched chain A.A. Deficiency of the alpha subunit of the BCKD complex causes Maple Syrup Urine Disease Type 1A, which is the MOST COMMON CAUSE OF MSUD.

BCKDHB: The official name of the BCKDHB gene is Branched chain keto acid dehydrogenase E1, beta polypeptide. BCKDHB gene mutation is similar to the BCKDHA mutation

The BCKDHB gene is located from base pair 80,816,343 to base pair 81,055,986 on chromosome 6. 

Most BCKDHB mutations insert or delete DNA in the gene. 

A special mutation is most common in people of Ashkenazi (eastern and central Europe) which consists of Jewish descent. This special mutation replaces the Arginine with Proline at position 183. 

This mutation disrupts the functionality of the BCKD complex and prevents it from breaking down the branched chain A.A. Deficiency of the beta subunit of the BCKD complex causes Maple Syrup Urine Disease Type 1B.

E2 complex: Dihydrolipoamide branched chain transacylase (E2) subunits are encoded by the DBT gene. Mutations in this gene lead to Maple Syrup Urine Disease Type 2.

E3 complex: Dihydrolipoamide dehydrogenase (E3) subunits are encoded by the DLD gene. Mutations in this gene lead to E3-deficient Maple Syrup Urine Disease. 

References

Gibson, L. R. (2001). Amino Acid Biosynthesis Inhibitors. Iowa State University. Retrieved July 12, 2012, from http://www.agron.iastate.edu/courses/Agron317/AA_inhibitors.htm
Brunetti-Pierri, N., Lanpher, B., Erez, A., Ananieva, E. A., Mohammad, I., Marini, J. C., . . . Lee, B. (1994). Phenylbutyrate therapy for maple syrup urine disease. Human Molecular Genetics, 20(4), 631–640.
Genetics Home Reference (2012, June 11). BCKDHA. Retrieved June 18, 2012, from http://ghr.nlm.nih.gov/gene/BCKDHA
Genetics Home Reference (2012, June 11). BCKDHB. Retrieved June 18, 2012, from http://ghr.nlm.nih.gov/gene/BCKDHB
Genetics Home Reference (2012, June 11). DLD. Retrieved June 18, 2012, from http://ghr.nlm.nih.gov/gene/DLD
Genetics Home Reference (2012, June 11). DBT. Retrieved June 18, 2012, from http://ghr.nlm.nih.gov/gene/DBT