Background: Antifreeze proteins bind to ice crystals and inhibit their growth. Results: The crystal structure of a potent beetle antifreeze protein was determined by direct methods. Conclusion: Ordered crystallographic waters on the protein surface match several planes of hexagonal ice. Significance: The structure is the largest determined ab initio without heavy atoms, and its ordered waters suggest a molecular basis for ice binding.

Background & Aims: Adult patients suffering from liver disease of unknown cause represent an understudied and underserved population. The use of whole-exome sequencing (WES) for the study of a broader spectrum of non-oncological diseases, among adults, remains poorly studied. We assessed the utility of WES in diagnosis and management of adults with unexplained liver disease despite comprehensive evaluation by a hepatologist and with no history of alcohol overuse. Methods: We performed WES and deep phenotyping of nineteen unrelated adult patients with idiopathic liver disease recruited at a tertiary academic health care center. Results: Analysis of the exome in 19 cases identified four monogenic disorders in five unrelated adults. Patient 1 suffered for 18 years from devastating complications of undiagnosed Type 3 Familial Partial Lipodystrophy due to a deleterious heterozygous variant in PPARG. Molecular diagnosis enabled initiation of leptin replacement therapy with subsequent normalization of liver

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BaCKgRoUND aND aIMS: Most of the genetic basis of chronic liver disease remains undiscovered.appRoaCH aND ReSUltS: To identify genetic loci that modulate the risk of liver injury, we performed genomewide association studies on circulating levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), and total bilirubin across 312,671 White British participants in the UK Biobank. We focused on variants associated with elevations in all four liver biochemistries at genome-wide significance (P < 5 × 10 −8 ) and that replicated using Mass General Brigham Biobank in 19,323 European ancestry individuals. We identified a genetic locus in mitochondrial glycerol-3-phosphate acyltransferase (GPAM rs10787429) associated with increased levels of ALT (P = 1.4 × 10 −30 ), AST (P = 3.6 × 10 −10 ), ALP (P = 9.5 × 10 −30 ), and total bilirubin (P = 2.9 × 10 −12 ). This common genetic variant was also associated with an allele dose-dependent risk of alcohol-associated liver disease (odd ratio [OR] = 1.34, P = 2.6 × 10 −5 ) and fatty liver disease (OR = 1.18, P = 5.8 × 10 −4 ) by International Classification of Diseases, 10th Revision codes. We identified significant interactions between GPAM rs10787429 and elevated body mass index in association with ALT and AST (P = 7.1 × 10 −9