Large copy-number variations in patients with statin-associated myopathy affecting statin myopathy-related loci.

Some patients are susceptible to statin-associated myopathy (SAM) either because of genetic variations affecting statin uptake and metabolism, or because they predispose their carriers to muscular diseases. Among the frequent variants examined using the genome-wide association study approach, SLCO1B1 c.521T>C represents the only validated predictor of SAM in patients treated with high-dose simvastatin. Our aim was to ascertain the overall contribution of large copy-number variations (CNVs) to SAM diagnosed in 86 patients. CNVs were detected by whole genome genotyping using Illumina HumanOmni2.5 Exome BeadChips. Exome sequence data were used for validation of CNVs in SAM-related loci. In addition, we performed a specific search for CNVs in the SLCO1B region detected recently in Rotor syndrome subjects. Rare deletions possibly contributing to genetic predisposition to SAM were found in two patients: one removed EYS associated previously with SAM, the other was present in LARGE associated with congenital muscular dystrophy. Another two patients carried deletions in CYP2C19, which may predispose to clopidogrel-statin interactions. We found no common large CNVs potentially associated with SAM and no CNVs in the SLCO1B locus. Our findings suggest that large CNVs do not play a substantial role in the etiology of SAM.

Mutations in PNPLA6 are linked to photoreceptor degeneration and various forms of childhood blindness.

Blindness due to retinal degeneration affects millions of people worldwide, but many disease-causing mutations remain unknown. PNPLA6 encodes the patatin-like phospholipase domain containing protein 6, also known as neuropathy target esterase (NTE), which is the target of toxic organophosphates that induce human paralysis due to severe axonopathy of large neurons. Mutations in PNPLA6 also cause human spastic paraplegia characterized by motor neuron degeneration. Here we identify PNPLA6 mutations in childhood blindness in seven families with retinal degeneration, including Leber congenital amaurosis and Oliver McFarlane syndrome. PNPLA6 localizes mostly at the inner segment plasma membrane in photoreceptors and mutations in Drosophila PNPLA6 lead to photoreceptor cell death. We also report that lysophosphatidylcholine and lysophosphatidic acid levels are elevated in mutant Drosophila. These findings show a role for PNPLA6 in photoreceptor survival and identify phospholipid metabolism as a potential therapeutic target for some forms of blindness.

Lipoprotein lipase deficiency: clinical, biochemical and molecular characteristics in three patients with novel mutations in the LPL gene.

Lipoprotein lipase (LPL) deficiency, caused by mutations in the LPL gene, is a rare autosomal recessive disorder manifesting in early childhood with recurrent abdominal pain, hepatosplenomegaly, acute pancreatitis, lipaemia retinalis and eruptive xanthomas. Typical laboratory findings are lactescent serum, extreme hypertriglyceridaemia and hypercholesterolaemia. The diagnostics is based on postheparin serum LPL assay and DNA analyses of the LPL gene. We report clinical, biochemical and molecular data of three children with LPL deficiency. One child manifested since the first week of life with recurrent abdominal pain (Patient 1), the second with abdominal distension and hepatosplenomegaly since the second month of life (Patient 3) and patient 2, asymptomatic younger brother of patient 1, was diagnosed in the first week of life. Lipaemia retinalis and splenomegaly were present in two symptomatic children, hepatomegaly in patient 3 and acute pancreatitis in patient 1. All children had lactescent serum, profound hypertriglyceridaemia (124 ± 25 mmol/l; controls < 2.2), hypercholesterolaemia (22.8 ± 7.3 mmol/l, controls < 4.2) and their LPL immunoreactive mass in serum did not increase after heparin injection. Molecular analyses revealed that both siblings are homozygous for novel mutation c.476C > G in the LPL gene changing the conserved amino acid of the catalytic centre. The third patient is a compound heterozygote for mutations c.604G>A and c.698A>G in the LPL gene, both affecting highly conserved amino acids. We conclude that LPL deficiency must be considered in neonates and young infants with abdominal pain and hypertriglyceridaemia because early treatment might prevent development of life-threatening acute pancreatitis.