Somatic cell hybridisation studies showing different gene mutations in Niemann-Pick variants

Abstract

Cultured skin fibroblasts from patients with different clinical types of Niemann-Pick disease were hybridized and sphingomyelinase activities were measured in the heterokaryon cell population. Both the natural substrate (3H-choline) sphingomyelin and the chromogenic analogue hexadecanoylamino-4-nitrophenylphosphorylcholine were used in the complementation analysis. In fusions between cells from type C Niemann-Pick disease with those from type A or B a clear restoration of sphingomyelinase activity occurred, whereas no complementation was found in other fusion combinations. The results indicate that at least two different genes are involved in the mutations leading to the different Niemann-Pick variants.

Niemann-Pick type B disease. Identification of a single codon deletion in the acid sphingomyelinase gene and genotype/phenotype correlations in type A and B patients.

“…In the following year, Schneider and Kennedy demonstrated that acid sphingomyelinase activity also was markedly decreased in patients with the milder, visceral form of Niemann-Pick disease now known as Type B disease (2). Subsequent biochemical analyses of additional patients confirmed these findings (10-12) and somatic cell genetic studies demonstrated that the mutations causing Types A and B disease were allelic (6). These findings stimulated investigators to speculate that the remarkable clinical heterogeneity observed among Type A and B Niemann-Pick disease patients The recent cloning and sequencing ofthe acid sphingomyelinase cDNA (15, 16) has permitted identification of the first mutations which result in Types A and B Niemann-Pick disease.…”

“…Two Receivedfor publication 7 March 1991 and in revisedform I May 1991. phenotypes (2)(3)(4)(5)(6). Type A Niemann-Pick disease is a severe neurodegenerative disorder ofinfancy characterized by progressive psychomotor retardation, hepatosplenomegaly, and death by three years of age.…”

Enzyme activities and phospholipid storage patterns in brain and spleen samples from niemann‐pick disease variants: a comparison of neuropathic and non‐neuropathic forms

“…In Gaucher disease specific mutations are reported (Ginns et al, 1982) to differentially affect the processing or subunit composition of [~-glucosidase in neuropathic and non-neuropathic types of the disease. To date no such evidence is available to explain the phenotypic expression in type A and type B NPD, although complementation studies have suggested these forms are allelic (Besley et al, 1980).…”

Isolation of cDNA clones encoding human acid sphingomyelinase: occurrence of alternatively processed transcripts.

“…NP-B is typically diagnosed in childhood and affected homozygotes may expire from respiratory disease complications in the second to fourth decade of life. Complementation studies performed by fusing NP-A and NP-B fibroblasts have shown that the mutations causing ASM deficiency in each subtype were allelic, since the enzymatic defect was not corrected in the somatic cell hybrids (Besley et al, 1980). However, the biochemical and molecular nature of the clinical heterogeneity resulting from deficient ASM activity remains an enigma.…”