The endoplasmic reticulum (ER) serves as a key hub for protein homeostasis, maintaining a strict quality-control system that ensures only properly folded proteins reach their destinations, while misfolded proteins are degraded via ER-associated degradation (ERAD) or selective ER-phagy. JKAMP, which encodes an ER-resident transmembrane protein involved in ERAD, has not previously been associated with human disease. Here, we report bi-allelic loss-of-function variants in JKAMP in 14 affected individuals from 10 unrelated families presenting with a neurodevelopmental syndrome characterized by intellectual disability, developmental delay, seizures, hypotonia, microcephaly, and dysmorphic features. An in vivo zebrafish model lacking jkamp recapitulated key aspects of the human disorder, including developmental abnormalities and impaired myelin production, further corroborating its pathogenic role. Mechanistic studies identified GPR37, a brain-enriched orphan G protein-coupled receptor (GPCR) and known JKAMP interactor, as a critical downstream effector. GPR37 plays essential roles in dopaminergic signaling, inflammatory pain regulation, neuroprotection, and myelination. Loss of JKAMP resulted in defective folding and degradation of GPR37, leading to its accumulation within the ER and impaired trafficking to the plasma membrane, likely due to impaired ER quality control. These findings establish JKAMP as a previously unrecognized contributor to human neurodevelopment and uncover a pathogenic mechanism linking ER protein quality control to GPCR regulation and neurological disease.

Surplus calories are used to prevent protein catabolism in patients with maple syrup urine disease (MSUD) but can also lead to obesity and its related complications. At present, there are no evidence-based guidelines to inform weight loss strategies for patients with inborn errors of metabolism. Obese MSUD patients often resist weight loss due to the fear of metabolic decompensation, and their dietary options are limited by dependence on medical foods with fixed nutritional composition. We examined the anthropometric and biochemical effects of metformin in nine adults with severe (classic) MSUD who were instructed to reduce their calorie intake from medical food by 10%. Eight participants (67% female) completed the 52-week study; one withdrew following elective liver transplantation. Baseline median age, body mass index (BMI), and glycosylated hemoglobin (HgbA1C) were 33.8 years (IQR 25.3–41.6), 38.3 kg/m² (IQR 31.6–42.2), and 5.3% (IQR 5.0–5.6), respectively. We titrated the daily metformin dose to a median of 2000 mg (IQR 1000–2000) by week 25, at which time seven (88%) participants successfully reduced total calories from medical food by 10%. Metformin was generally well tolerated. Diarrhea was the most common treatment-related complication, affecting 56% of participants, and limited dose escalation in two (22%) of them. No participant achieved the primary outcome of a > 10% BMI change. However, metformin therapy allowed for modest and significant reductions in weight (−2.8%, p = 0.023), BMI (−2.8 kg/m2, p = 0.016), and calories from medical food without altering plasma leucine concentrations or the proportion of dietary protein from intact sources. Serum triglycerides, high-density lipoprotein, and HgbA1C did not change over the study period. Based on these clinical observations, we conclude that classic MSUD patients can safely use metformin to aid weight loss without triggering metabolic instability, and may therefore tolerate more aggressive weight loss strategies.

Sorbitol dehydrogenase (SORD) deficiency, due to biallelic loss-of-function variants in the SORD gene, is a recently recognized cause of autosomal recessive hereditary neuropathy. Specific diagnosis is difficult on clinical grounds alone, and molecular genetic testing of SORD is complicated by the presence of a pseudogene. Biochemical testing of serum sorbitol is suggested as a potential biomarker. We report a novel urine biochemical profile of elevated excretion of sorbitol and a second polyol, xylitol, to aid in the identification of individuals with SORD-related neuropathy.

Congenital pancreatic lipase deficiency (CPLD, OMIM #614338) is a rare exocrine pancreatic disorder presenting in late infancy with steatorrhea, fat-soluble vitamin deficiency, and low pancreatic lipase activity. Variants of the pancreatic triglyceride lipase (PNLIP) gene have been linked to CPLD. Six children from four Amish families exhibited CPLD symptoms and two had decreased fecal elastase levels when tested. A novel homozygous PNLIP variant, c.869G>A (p.S290N), was identified in these children. This study aimed to characterize the PNLIP variant to understand its mechanism underlying CPLD. The variant impact was first evaluated using computational modeling. Functional analyses included activity assays, cellular PNLIP partition assessments, and endoplasmic reticulum (ER) stress evaluation in transfected cells. Computational modeling showed that p.Ser290 is highly conserved across species and the variant causes steric hindrance resulting in protein misfolding. Functional assays revealed that the PNLIP variant had a complete loss of activity compared to the wild type (WT), with defects in catalytic function and secretion. Immunoblotting showed reduced PNLIP variant in the medium and increased accumulation in the detergent-insoluble fraction consistent with protein misfolding. Variant-expressing cells had elevated levels of BiP, an ER stress marker, and increased Xbp1 mRNA splicing, suggesting an elevated ER stress and unfolded protein response (UPR). In conclusion, the PNLIP p.S290N variant causes CPLD through a loss-of-function mechanism, characterized by loss of enzymatic activity and defective secretion due to protein misfolding. Further studies are needed to determine whether the misfolding variant protein induces proteotoxicity, potentially increasing the risk of pancreatic injury including chronic pancreatitis.

The Amish of Lancaster County, PA has been the focus of genetic studies for many years due to its demographic history and unique genetic makeup that includes a historical bottleneck event and subsequent genetic drift, resulting in a marked decrease in genetic diversity and increased frequency of some variants that have substantially shaped the health of the community. To characterize the coding variation in the Amish genome, we sequenced the exomes of 7221 adult community members, and in this report, we contrast genetic diversity between the Amish and Europeans from the UK Biobank. Exome sequences of 7221 Amish contained only 14% as many variants as the same number of UKB participants. This reduced genetic diversity has substantial clinical implications. We identified pathogenic (P) and likely pathogenic (LP) variants from ClinVar and a population-specific genetic screening panel and found that most of the variants present in the Amish were highly enriched, resulting in 5.2% of Amish individuals being homozygous for a recessive P/LP variant and 25.6% being heterozygous for at least one dominant P/LP variant. In 43.6% of the 2141 Amish spouse-pairs in our sample, at least one spouse was heterozygous for a P/LP dominant variant, and 24.3% of couples were autosomal recessive disease carrier couples, meaning that each of their children was at ~25% risk of inheriting two copies of that variant. Gene discovery efforts in other founder communities will likely uncover distinct P (and beneficial) variants impacting the health of these communities, with implications for all of human health.

Complement factor I (CFI) deficiency is an ultra-rare inborn disorder of complement regulation that manifests with protean infectious, vasculitic, and neuroinflammatory symptoms. To functionally validate a previously unrecognized, disease-associated CFI variant (Y459S) and determine variant enrichment in the Old Order Amish population.

Partial RAG deficiency (pRD) can manifest with systemic and tissue-specific immune dysregulation, with inflammatory bowel disease (IBD) in 15% of the patients. We aimed at identifying the immunopathological and microbial signatures associated with IBD in patients with pRD and in a mouse model of pRD (Rag1^w/w) with spontaneous development of colitis. pRD patients with IBD and Rag1^w/w mice showed a systemic and colonic Th1/Th17 inflammatory signature. Restriction of fecal microbial diversity, abundance of pathogenic bacteria, and depletion of microbial species producing short-chain fatty acid were observed, which were associated with impaired induction of lamina propria peripheral Treg cells in Rag1^w/w mice. The use of vedolizumab in Rag1^w/w mice and of ustekinumab in a pRD patient were ineffective. Antibiotics ameliorated gut inflammation in Rag1^w/w mice, but only bone marrow transplantation (BMT) rescued the immunopathological and microbial signatures. Our findings shed new light in the pathophysiology of gut inflammation in pRD and establish a curative role for BMT to resolve the disease phenotype.