Mutational spectrum of the CHAC gene in patients with chorea-acanthocytosis

Area of Science:

• Genetics
• Neuroscience
• Biochemistry

Background:

• Chorea-acanthocytosis (ChAc) is an autosomal recessive neurological disorder.
• Characteristic features include hyperkinetic movements and abnormal red blood cell morphology.
• Mutations in the CHAC gene are the cause of ChAc.

Purpose of the Study:

• To screen all 73 exons and flanking intronic sequences of the CHAC gene for mutations in 43 probands with ChAc.
• To identify and characterize novel mutations in the CHAC gene.
• To correlate mutation type and distribution with disease presentation.

Main Methods:

• Denaturing high-performance liquid chromatography (DHPLC) was used to screen for mutations.
• All 73 exons plus flanking intronic sequences of the CHAC gene were analyzed.
• Genetic analysis was performed on 43 probands with ChAc.

Main Results:

• 57 different mutations were identified in 39 probands, with 54 being novel.
• Mutations included 15 nonsense, 22 insertion/deletion, 15 splice-site, and 2 missense mutations.
• Mutations were distributed throughout the CHAC gene, with three recurring mutations found in multiple families.

Conclusions:

• The identified mutations in the CHAC gene provide further insight into the genetic basis of ChAc.
• The high proportion of mutations predicted to cause absence of gene product supports the recessive inheritance pattern.
• The CHAC protein, chorein, shows some tolerance to amino acid substitutions, with only two missense mutations appearing pathogenic.