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Autosomal recessive hypercholesterolemia (ARH) is characterized by elevated LDL serum levels, xanthomatosis, and premature coronary artery disease. Three loci have been described for this condition (1p35, 15q25-q26 and 13q). Recently, the responsible gene at the 1p35 locus, encoding an LDL receptor adaptor protein (ARH) has been identified. We studied a Mexican ARH family with two affected siblings. Sequence analysis of the ARH gene (1p35 locus) revealed that the affected siblings are homozygous for a novel mutation (IVS4+2T>G) affecting the donor splice site in intron 4, whereas both the parents and an unaffected sister are heterozygous for this mutation. The IVS4+2T>G mutation results in a major alternative transcript derived from a cryptic splice site, which carries an in-frame deletion of 78 nucleotides in the mature mRNA. The translation of this mRNA yields a mutant protein product (ARH-26) lacking 26 amino acids, resulting in the loss of beta-strands beta6 and beta7 from the PTB domain. This is the first case where a naturally occurring mutant with an altered PTB domain has been identified.

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In contrast to their counterparts in bacteria and animals the soluble inorganic pyrophosphatases from plant cells are active as monomers. The isoforms 1 and 4 from <em>Arabidopsis thaliana</em> have been characterized with more detail, but their three-dimensional structure is unavailable. Here, a recently published protocol (ROSETTA design-HMMer), is used to guide well-known techniques for homology-modeling, in the production of reliable models for the three-dimensional structure of these two arabidopsis isoforms. Their interaction with magnesium ions and pyrophosphate is analyzed <em>in silico</em>in silico.

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