In a 12-year-old patient with cholesteryl ester storage disease (CESD; 278000) from a nonconsanguineous Polish-German family, Klima et al. (1993) detected a 72-bp in-frame deletion resulting in the loss of amino acid codons 254 through 277. Analysis of genomic DNA revealed that the 72 bp represented an exon, indicating that the deletion in the mRNA was caused by defective splicing. Sequence analysis of the patient's genomic DNA revealed a G-to-A substitution in the last nucleotide of the 72-bp exon on 1 allele. No normal-sized mRNA was detectable in the propositus even though he was not homozygous for the splice site mutation. Klima et al. (1993) concluded that the patient was compound heterozygous for the splice site mutation and a null allele. The patient showed LIPA activity in cultured skin fibroblasts approximately 9% of normal. Hepatosplenomegaly had been present since age 5 years.
Aslanidis et al. (1996) restudied the patient of Klima et al. (1993) and defined the splice site mutation as a G-to-A mutation at position -1 of the splice donor site following exon 8, resulting in incorrect splicing and the removal of the 72-bp exon 8 of the LIPA gene. They determined that the other allele of the patient carried a premature termination mutation (613497.0003) as well as the L179P mutation (613497.0001); the LIPA mRNA was rendered unstable by the premature stop codon. Aslanidis et al. (1996) demonstrated that the splice site mutation allowed the production of approximately 3 to 4% of correctly spliced mRNA relative to wildtype. Aslanidis et al. (1996) also identified a mutation at the same splice donor site, and also resulting in deletion of exon 8, in 2 sibs with Wolman disease; that mutation, at the +1 position, allowed no correct splicing, and patient fibroblasts were devoid of enzymatic activity. See 613497.0005.
In 2 sibs with CESD, Maslen and Illingworth (1993) and Maslen et al. (1995) identified compound heterozygosity for this splice site mutation in the LIPA gene, inherited from their father, and the L179P mutation (613497.0001). The affected children were a sister and brother who presented with idiopathic hepatomegaly at ages 6 and 8 years, respectively. Subsequent analyses indicated that they also had hypercholesterolemia and a severe reduction in cholesteryl ester hydrolase activity in cultured fibroblasts.
Muntoni et al. (1995) observed homozygosity for the splice site mutation (Klima et al., 1993) in a Spanish kindred with cholesterol ester storage disease. Exon 8 of the LIPA gene was deleted.
