Trial Information

Prevalence of a Non-Expressing 11B Mutation in Aka Peoples of the Central African Republic

The CCCH tandem zinc finger proteins are members of a small family of proteins that regulate
the stability of certain types of mRNA containing so-called class II AU-rich elements in
their 3'-untranslated regions. The best studied member of this protein family,
tristetraprolin (TTP), exerts this destabilizing effect on at least two mRNAs coding for
physiologically and medically important cytokines, tumor necrosis factor alpha and
granulocyte macrophage colony stimulating factor. The physiological functions of the other
two members of this protein family in mammals, 11B and 11D, are not known, but in
experimental transfection studies they too can destabilize mRNAs containing this type of
AU-rich element.

As part of the Environmental Genome Project, we resequenced the protein coding portions of
the human genes encoding these three proteins, and uncovered a dinucleotide splice site
mutation in the 11B gene in one of 144 alleles sequenced. We showed that this mutation
created a novel restriction fragment length polymorphism, and that this mutation resulted in
the failure of splicing and expression of the mRNA encoded by the mutant allele. Based on
our previous data with mice completely deficient in TTP, we anticipate that complete
deficiency of this protein, and possibly its partial deficiency, would result in human
disease.

The mutant allele was from an anonymous adult Aka Pygmy women from the Central African
Republic. We propose to genotype up to 1000 members of this ethnic group after obtaining
buccal cell DNA from them. This will give us an approximate idea of the prevalence of this
mutation in this population. If the mutation is found in a significant number of living
individuals in this initial screen, then we will propose a later study of the individuals
who have this genotype and their families. This second study, which will be reviewed
separately, will attempt to correlate this genotype with a human trait or phenotype and
possible treatable human disease.