Neutral Lipid Storage Disease with Myopathy: disease modeling using patients’ hiPSc

Domenico Antonio Coviello, Sara Missaglia, Mauro Castagnetta, Elena Maria Pennisi, Massimo Mogni, Daniela Tavian

Risultato della ricerca: Contributo in libroContributo a convegno


Mutations in the PNPLA2 gene cause the onset of Neutral Lipid Storage Disease with Myopathy (NLSD-M), a rare autosomal recessive disorder characterized by an abnormal accumulation of triacylglycerol into cytoplasmic lipid droplets (LDs). In most tissues the LDs are cellular organelles for the triacylglycerol storage. LDs metabolic functions are mediated by proteins bound to their surface. In particular, the lipase that catalyzes the removal of the first acyl chain from triacylglycerol is the adipose triglyceride lipase (ATGL), also known as patatin-like phospholipase domain-containing protein 2 (PNPLA2). To our best knowledge, twenty six different PNPLA2 mutations have been described in thirty two NLSD-M patients. NLSD-M patients are mainly affected by progressive myopathy, cardiomyopathy and hepatomegaly. However, their clinical severity appears to be highly variable. Other clinical symptoms may include diabetes, chronic pancreatitis and short stature. NLSD-M has, at present, no specific therapy. We have previously reported clinical and genetic findings of some NLSD-M patients obtaining dermal biopsies from them. Here we report the development of hiPSc (human induced pluripotent stem cell) from patients’ fibroblasts harboring different PNPLA2 mutations. The first patient was found to be homozygous for a deletion at nucleotide 542 (c.542delAC). This deletion caused a premature stop codon at position 212. The molecular analysis of patient 2 showed a homozygous missense mutation, c.662G>C (p.R221P). Initial hiPSc colony selection was based on morphologic evaluation and on detection of pluripotency surface markers (SSEA-4 and TRA-1-81). HiPSc also expressed undifferentiated ES cell markers (NANOG, SOX2 and OCT4). Moreover, embryoid bodies (EBs) have been generated from NLSD-M-iPSCs to assess the pluripotent properties of these cells. Karyotypic analysis of hiPSc lines indicated a normal complement of chromosomes. Immunohystochemical evaluations of LDs on hiPSc revealed that they recapitulate pathological hallmark of the disease. We propose use of inherently patients- and disease specific hiPSc to study the pathogenetic mechanisms leading to NLSD-M and as a potential model for therapeutic evaluation.
Lingua originaleEnglish
Titolo della pubblicazione ospiteAbstracts ASHG meeting 2014
Stato di pubblicazionePubblicato - 2014
EventoAmerican Society of Human Genetics Annual Meeting - San Diego
Durata: 18 ott 201422 ott 2014


ConvegnoAmerican Society of Human Genetics Annual Meeting
CittàSan Diego


  • cellular model
  • human fibroblast reprogramming
  • human induced pluripotent stem cell
  • neutral lipid storage disease


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