Niemann-Pick C1 disease: The I1061T substitutions a frequent mutant allelein patients of Western European descent and correlates with a classic juvenile phenotype

Niemann-Pick type C (NPC) disease is an autosomal recessive lipid-storage d isorder usually characterized by hepatosplenomegaly and severe progressive neurological dysfunction, resulting from mutations affecting either the NPC 1 gene (in 95% of the patients) or the yet-to-be-identified NPC2 gene. Our initial study of 25 patients with NPC1 identified a T-3182-->C transition t hat leads to an I1061T substitution in three patients. The mutation, locate d in exon 21, affects a putative transmembrane domain of the protein. PCR-b ased tests with genomic DNA were used to survey 115 unrelated patients from around the world with all known clinical and biochemical phenotypes of the disease. The I1061T allele constituted 33 (14.3%) of the 230 disease-causi ng alleles and was never found in controls (>200 alleles). The mutation was particularly frequent in patients with NPC from Western Europe, especially France (11/62 alleles) and the United Kingdom (9/32 alleles), and in Hispa nic patients whose roots were in the Upper Rio Grande valley of the United States. The I1061T mutation originated in Europe and the high frequency in northern Rio Grande Hispanics results from a founder effect. All seven unre lated patients who were homozygous for the mutation and their seven affecte d siblings had a juvenile-onset neurological disease and severe alterations of intracellular LDL-cholesterol processing. The mutation was not found (0 /40 alleles) in patients with the severe infantile neurological form of the disease. Testing for this mutation therefore has important implications fo r genetic counseling of families affected by NPC.