A 2-bp deletion mutation in SMPD1 gene leading to lysosomal acid sphingomyelinase deficiency in a Chinese consanguineous pedigree

J Pediatr Endocrinol Metab. 2022 May 27;35(8):1113-1116. doi: 10.1515/jpem-2021-0480. Print 2022 Aug 26.

PMID: 35617710

Han Kang, Min Zhou, Chengxiu Xie

Highlights: This study reports a c.1420_1421del mutation in SMPD1 gene which caused ASM activity decrease.

Abstract

Objectives: An autosomal recessive sphingolipidosis called Niemann-Pick disease type A (NPDA, MIM: 257200) is brought on by the deficiency of lysosomal acid sphingomyelinase (ASM). Imprinted genes like TSSC5, TSSC3, and ZNF215 that flank the SMPD1 gene have been reported to be present in a group of genes at chromosome 11p15. Recent investigations have suggested that the paternally imprinted and maternally selectively expressed SMPD1 gene.

Case presentation: A five-month-old boy with severe anemia, hepatosplenomegaly and bone marrow foam cells was recruited from a complete cousin couple. ASM activity and SMPD1 gene sequencing were carried out on available members of this lineage, including the proband, his parents, and his sister, to ascertain whether the boy had NPDA. In comparison to healthy controls (204.5 nmol/h/g-protein), the ASM activities of the proband and parents were deficient (17.7 nmol/h/g-protein) and approximately 50% lower (83.3 nmol/h/g-protein), respectively. The proband's homozygous mutation in the SMPD1 gene, c.1420_1421del, results in an open reading frameshift and a premature stop codon. At this location, the parents and a few members of this family showed heterozygous mutation. In order to determine whether the SMPD1 gene is imprinted as previously reported, the expression of RNA level was examined in all of the available family members. The individuals that had the heterozygous c.1420_1421del mutation demonstrated that both the maternal and paternal inherited alleles were expressed.

Conclusions: This study identified a c.1420_1421del mutation in the SMPD1 gene that decreased ASM activity. This locus was expressed biallelically in heterozygous individuals, suggesting that SMPD1 is not imprinted in this family.

Keywords: Niemann–Pick disease, SMPD1, imprint