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 y treatable human disease.