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Mol Genet Metab. 2019 Jun 15. pii: S1096-7192(19)30196-9. doi: 10.1016/j.ymgme.2019.06.005. [Epub ahead of print]

The novel synonymous variant in LIPA gene affects splicing and causes lysosomal acid lipase deficiency.

Author information

1
Federal State Budgetary Institution «Research Centre for Medical Genetics», Moscow, Russia. Electronic address: bychkov.nbo@gmail.com.
2
Federal State Budgetary Institution «Research Centre for Medical Genetics», Moscow, Russia.
3
Federal State Budgetary Institution Children's Clinical Hospital of the Russian Federation Ministry of Health, Moscow, Russia.
4
Federal State Budgetary Institution «Federal Research Center for Nutrition and Biotechnology», Moscow, Russia; Federal State Budgetary Institution «Pirogov Russian National Research Medical University», Moscow, Russia.
5
Federal State Autonomous Institution «National Medical Research Center for Children's Health» of the Russian Federation Ministry of Health, Moscow, Russia.

Abstract

Lysosomal acid lipase deficiency (LALD; MIM#278000) is a continuum of autosomal recessive diseases caused by defects in the gene LIPA and historically divided into two phenotypes: severe infantile-onset form called Wolman disease (WD) and childhood/adult-onset form known as cholesteryl ester storage disease (CESD). We report a novel synonymous homozygous variant c.600G > A in LIPA of a patient with LALD. Functional analysis of the patient cDNA and minigene assay revealed this variant as the cause of exonic cryptic splice site activation and 63 b.p. deletion in exon 6. To investigate the impact of this in-frame deletion on protein function, we performed 3D modeling of the human lysosomal acid lipase and showed the alteration of highly conservative region in close proximity to protein active site, which may completely eliminate the enzymatic activity. Using transcript specific real-time quantitative PCR method, we evaluated the relative ratio of the patient's wild type transcript isoform which is significantly reduced and correlates with severe childhood-onset variant of LALD.

KEYWORDS:

Cholesteryl ester storage disease; Cryptic splice site; Functional analysis; Minigene assay; Quantitative real-time PCR

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