MYOPATHIC MITOCHONDRIAL DNA DEPLETION SYNDROME
RRM2B Sequencing
MITOCHONDRIAL DNA ANALYSIS
Also see: SUCLA2 Sequencing; Thymidine Kinase TK2 Sequencing; SUCLG1 Sequencing

Description:

The RRM2B gene encodes the small subunit of p53-inducible ribonucleotide reductase (P53R2), a heterotetrameric enzyme responsible for de novo conversion of ribonucleoside diphosphates ( rNDPs) into the corresponding deoxyribonucleoside diphosphates ( dNDPs) that are essential for DNA synthesis. RRM2B plays a crucial role in dNTP supply, especially for the synthesis of mtDNA. Homozygous and compound heterozygous mutations have been reported in autosomal recessive, severe, encephalomyopathic form of mitochondrial DNA (mtDNA) depletion syndrome. Patients had mtDNA depletion in skeletal muscle and died in early months of life with severe lactic acidosis. Experiments with animal model suggested that p53R2 has a pivotal role in maintaining dNTP levels for DNA repair in resting cells. Impairment of this pathway may enhance spontaneous mutation frequency and activate p53-dependent apoptotic pathways in vivo, causing severe renal failure, growth retardation, and early mortality. Human RRM2B gene is mapped to chromosome chromosome 8q23.1. It contains 9 exons and encodes for 351 amino acids. To date, only 5 different missense mutations have been reported.

An encephalomyopathic form of mtDNA depletion syndrome can be also be caused by mutation in the succinyl-CoA synthase gene (SUCLA2) on chromosome 13q.

Reasons for Referral:

Confirmation of a clinical diagnosis
Carrier testing
Prenatal diagnosis for known familial mutations

Testing Methodology:

The exons and flanking intronic regions of the RRM2B gene are PCR amplified and sequenced in both the forward and reverse directions.

Specimen Requirements:

Blood: EDTA (purple-top) tubes: Adult: 14 cc; Child: 6 cc; Infant: 2-3 cc
Requisition form must accompany the specimen. To receive forms, additional information or specimen collection kits, please contact the laboratory. Please call laboratory for specific requirements for prenatal testing.

Turnaround Time:

Index: 4 weeks
Known Familial Mutation: 2 weeks

CPT Codes and Prices:

Index: 83891, 83904x18, 83898x9, 83912, 83894x2
Known Familial Mutation: 83904x4, 83898x2, 83912, 83891, 83894x2

Shipping Information

Forms:

>> Gene Sequencing Requisition or Mitochondrial Requisition - Mitochondrial Diagnostic Checklist is included
>> Prenatal Requisition

References:

1. Bourdon, A.; Minai, L.; Serre, V.; Jais, J.-P.; Sarzi, E.; Aubert, S.; Chretien, D.; de Lonlay, P.; Paquis-Flucklinger, V.; Arakawa, H.; Nakamura, Y.; Munnich, A.; Rotig, A. : Mutation of RRM2B, encoding p53-controlled ribonucleotide r eductase (p53R2), causes severe mitochondrial DNA depletion. (Letter) Nature Genet. 39: 776-780, 2007. PubMed ID: 17486094
2. Kimura, T.; Takeda, S.; Sagiya, Y.; Gotoh, M.; Nakamura, Y.; Arakawa, H. : Impaired function of p53R2 in Rrm2b-null mice causes severe renal failure through attenuation of dNTP pools. Nature Genet. 34: 440-445, 2003. PubMed ID: 12858174
3. Tanaka, H.; Arakawa, H.; Yamaguchi, T.; Shiraishi, K.; Fukuda, S.; Matsui, K.; Takei, Y.; Nakamura, Y. : A ribonucleotide reductase gene involved in a p53-dependent cell-cycle checkpoint for DNA damage. Nature 404: 42-49, 2000. PubMed ID: 10716435

Test Codes:

Index: 3420
Known Familial Mutation: 3421
Prenatal: 3422