G123e

European

*Zeng et al, 2002; Novel mutations are underlined.

*Zeng et al, 2002; Novel mutations are underlined.

Within exon 2, a run of seven adenines occurs at positions 238-244 that is prone to slipped mispairing at the replication fork. The seventh adenine at nucleotide 244 was deleted in one of our patients and in another, 244-245AT was deleted. In two other patients, we encountered insertion of an adenine at position 245, previously described by others. Hence, this site tends to be associated with both insertion and deletion, leading in both cases to a truncated non-functional gene product.

We identified a normal mutation in the cystine residue at position 152 (C152W) which resulted in complete deficiency of ASPA activity on in vitro mutagenesis and expression in COS-7 cells. As noted (Zeng et al., 2002) the C152 residue participates in the creation of a strong P-sheet structure and may be required for maintaining ASPA in a conformationally active state (Kaul et al., 1995). The existence of two other mutations in this same residue, i.e. C152R (Kaul, et al., 1995) and C152Y (Kaul, et al., 1996), highlights the importance of this site for the structural integrity of ASPA.

Several missense mutations resulted in a change in electron charge of the substituted amino acid or conversion of a polar amino acid to a hydrophilic one. These included D68A (aspartate ^alanine), N121I (asparagine^isoleucine) T166I (threonine ^iso-leucine), and D249V (aspartate^valine). In the case of D68A expression of the mutant cDNA did not produce any ASPA activity in COS-7 cells. All 12 novel missense mutations are in conserved regions of the ASPA gene.

Homozygosity for these rare novel mutations was found in the cases of G18R C152W, H244R, 244 del AT, X314W and 698 ins C. Consanguinity was present only for the 698 ins C mutation (Yemenite). While an ethnic predilection for each of these mutations is a possibility, only for two of the mutations, H244R and D249V, were they present in more than one patient of the same ethnic origin.

Table 3. Mutations in non-Jewish CD Patients*

Patient

Mutation 1

Mutation 2

Ethnic origin

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