Growth Regulation, Acid Sphingomyelinase Gene and Genomic Imprinting: Lessons from an Experiment of Nature


Independent Research Group for Genetics -and Immunology, Budapest, Hungary


The author investigated the possible role of acid sphingomyelinase (ASM) gene (SMPD1) in the regulation of growth, in connection with an experiment of nature. The association of a decreased ASM activity and an overgrowth disorder, Beckwith-Wiedemann Syndrome (BWS) with hemihypertrophy has been described at a 23 months old boy in a recent case report (Réthy et al, in this issue). ASM catalyses the production of ceramide, a key molecule of apoptosis, from sphingomyelin. Based on these data it is suggested that the ASM gene (SMPD1) can suppress/counterbalance the anti-apoptotic effects of BWSrelated growth-promoters, like IGF-II, under normal circumstances. Recent literary data support this view. ASM deficient lymphoblasts derived from patients with Niemann-Pick disease (NPD) fail to undergo apoptosis in response to external signals and Fas cross-linking. BWS-related genes are considered to be regulated by genomic imprinting. Therefore the author compared some characteristics of both SMPD1 and imprinted genes. The analyzed features of SMPD1 gene (few and small introns, Alu 1 repeat element, CC-rich regulatory region, alternative splicing) are characteristic to imprinted genes. Hemihypertrophy, mentioned in the referred BWS-case, is distinctive to the involvement of the maternal allele of the second BWS chromosomal region (BWSCR2) at 11p15.3. The SMPDI gene has been localized just distal to the B05 breakpoint of BWSCR2. Furthermore, in BWS-associated tumors, the loss of heterozygosity (LOH) found on 11p15 was always maternal. Thus, in the case referred to with ASM deficiency the maternal allele has certainly been effected. These conclusions are in accordance with the 'cluster-model of imprinting' as well as with the conflict theory of imprinting. Taken together, the above mentioned clinical and experimental data suggest that SMPD1, most likely at 11p15.4, is an imprinted, maternally expressed, BWS- and apoptosis-related growth suppressor gene. Further studies are necessary to prove this hypothesis. Pathology & Oncology Research, Vol 6, Nr 4, 298-300, 2000

Key words: acid shingomyelinase; ceramide; Beckwith-Wiedemann Syndrome; growth regulation; apoptosis; conflict theory; imprinting in clusters

Received: Oct 12, 2000; accepted: Dec 13, 2000
Correspondence: Lajos A RÉTHY, Independent Research Group for Genetics -and Immunology, , HRC-Bethesda Children's Hospital, Bethesda u. 3. Budapest 1146, Hungary; Tel: +36-13649070, Fax: +36-13649070; E-mail:

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