Abstract
Genetic lipodystrophies are a group of rare syndromes associated with major metabolic complications – including severe insulin resistance, type 2 diabetes mellitus, and hypertriglyceridemia – which are classified according to the distribution of adipose tissue. Lipodystrophies can be present at birth or develop during life and can range from local to partial and general. With at least 18 different genes implicated so far, definite diagnosis can be challenging due to clinical and genetic heterogeneity. In an adult female patient with clinical and metabolic features of partial lipodystrophy we identified via whole genome sequencing (WGS) a single complex AGPAT2 allele [V67M;V167A], functionally equivalent to heterozygosity. AGPAT2 encodes for an acyltransferase implicated in the biosynthesis of triacylglycerol and glycerophospholipids. So far homozygous and compound heterozygous mutations in AGPAT2 have only been associated with generalized lipodystrophy. A SNP risk score analysis indicated that the index patient is not predisposed to lipodystrophy based on her genetic background. The partial phenotype in our patient is therefore more likely associated to the genetic variants in AGPAT2. To test whether the resulting double-mutant AGPAT2 protein is functional we analyzed its in vitro enzymatic activity via mass spectrometry. The resulting AGPAT2 double mutant is enzymatically inactive. Our data support the view that the current classification of lipodystrophies as strictly local, partial or generalized may have to be re-evaluated and viewed more as a continuum, both in terms of clinical presentation and underlying genetic causes. Better molecular understanding of lipodystrophies may lead to new therapies to treat adipose tissue dysfunction in common and rare diseases.
Highlights
The absence and/or loss of adipose tissue is the hallmark of genetic lipodystrophies, a clinically and genetically heterogeneous group of extremely rare syndromes (Visser et al, 2011; Lightbourne and Brown, 2017)
P.V167A, respectively (Supplementary Figure 1). These genetic variants were absent in the variation databases (NHLBI GO Exome Sequencing Project (ESP), 2016) (Exome Variant Server), 1000Genomes (1000 Genomes Project Consortium, 2015), and Single Nucleotide Polymorphism Database (Sherry et al, 2001)
The Genome Aggregation Database (gnomAD) database contains exomes and genomes of individuals that are not necessarily healthy: Individuals with severe pediatric diseases have been removed, but many remaining individuals suffer from adult-onset diseases such as type 2 diabetes mellitus (T2DM), a condition that is associated with lipodystrophy (Lek et al, 2016)
Summary
The absence and/or loss of adipose tissue is the hallmark of genetic lipodystrophies, a clinically and genetically heterogeneous group of extremely rare syndromes (Visser et al, 2011; Lightbourne and Brown, 2017). Two major categories can be distinguished: Familial partial lipodystrophy (FPLD) and congenital generalized lipodystrophy (CGL). Mutations in the genes LMNA and PPARG are the main genetic causes of FPLD (Garg, 2011). Patients with the autosomal recessive condition CGL often present in the neonatal period or early childhood with a generalized loss of adipose tissue. The majority of the patients with CGL (∼95%) harbors mutations in the genes AGPAT2 (CGL1; OMIM 603100) and BSCL2 (CGL2; OMIM 606158). There is considerable clinical and genetic heterogeneity, making a definite diagnosis challenging (Patni and Garg, 2015)
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