Niemann-Pick C1 disease: the I1061T substitution is a frequent mutant allele in patients of Western European descent and correlates with a classic juvenile phenotype

Abstract

Niemann-Pick type C (NPC) disease is an autosomal recessive lipid-storage disorder usually characterized by hepatosplenomegaly and severe progressive neurological dysfunction, resulting from mutations affecting either the NPC1 gene (in 95% of the patients) or the yet-to-be-identified NPC2 gene. Our initial study of 25 patients with NPC1 identified a T3182-->C transition that leads to an I1061T substitution in three patients. The mutation, located in exon 21, affects a putative transmembrane domain of the protein. PCR-based 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-causing 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 Hispanic 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 unrelated patients who were homozygous for the mutation and their seven affected 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 for genetic counseling of families affected by NPC.

Figure 1

Sequence of NPC1 exon 21 with intron boundaries, depicting the location of the T₃₁₈₂→C transition and the design of primers for detection of the mutation by creation of a Rsa I restriction site. Intronic sequences are in lowercase characters; exonic sequences are in uppercase.The asterisk (*) indicates the base change made in the forward primer to introduce a RsaI restriction site when the adjacent T→C base change is present.

Figure 2

Restriction analysis of the I1061T mutation in a representative family. In presence of the mutation, Rsa I digestion of the 147-bp PCR product generates a 122-bp fragment. The results presented are those in family 1 (see table 3). Mk indicates molecular-mass DNA marker (100 and 200 bp); Fa, father; Mo, mother; P1, P2, P3, P4, affected siblings; Contr, normal subject. The plus sign (+) denotes the presence of a I1061T allele; the minus sign (−) denotes its absence.