Biallelic Cys141Tyr variant of SEL1L is associated with neurodevelopmental disorders, agammaglobulinemia, and premature death.

Suppressor of lin-12-like-HMG-CoA reductase degradation 1 (SEL1L-HRD1) ER-associated degradation (ERAD) plays a critical role in many physiological processes in mice, including immunity, water homeostasis, and energy metabolism; however, its relevance and importance in humans remain unclear, as no disease variant has been identified. Here, we report a biallelic SEL1L variant (p. Cys141Tyr) in 5 patients from a consanguineous Slovakian family. These patients presented with not only ERAD-associated neurodevelopmental disorders with onset in infancy (ENDI) syndromes, but infantile-onset agammaglobulinemia with no mature B cells, resulting in frequent infections and early death. This variant disrupted the formation of a disulfide bond in the luminal fibronectin II domain of SEL1L, largely abolishing the function of the SEL1L-HRD1 ERAD complex in part via proteasomal-mediated self destruction by HRD1. This study reports a disease entity termed ENDI-agammaglobulinemia (ENDI-A) syndrome and establishes an inverse correlation between SEL1L-HRD1 ERAD functionality and disease severity in humans.

N-Glycoprofiling of SLC35A2-CDG: Patient with a Novel Hemizygous Variant.

Congenital disorders of glycosylation (CDG) are a group of rare inherited metabolic disorders caused by a defect in the process of protein glycosylation. In this work, we present a comprehensive glycoprofile analysis of a male patient with a novel missense variant in the SLC35A2 gene, coding a galactose transporter that translocates UDP-galactose from the cytosol to the lumen of the endoplasmic reticulum and Golgi apparatus. Isoelectric focusing of serum transferrin, which resulted in a CDG type II pattern, was followed by structural analysis of transferrin and serum N-glycans, as well as the analysis of apolipoprotein CIII O-glycans by mass spectrometry. An abnormal serum N-glycoprofile with significantly increased levels of agalactosylated (Hex3HexNAc4-5 and Hex3HexNAc5Fuc1) and monogalactosylated (Hex4HexNAc4 ± NeuAc1) N-glycans was observed. Additionally, whole exome sequencing and Sanger sequencing revealed de novo hemizygous c.461T > C (p.Leu154Pro) mutation in the SLC35A2 gene. Based on the combination of biochemical, analytical, and genomic approaches, the set of distinctive N-glycan biomarkers was characterized. Potentially, the set of identified aberrant N-glycans can be specific for other variants causing SLC35A2-CDG and can distinguish this disorder from the other CDGs or other defects in the galactose metabolism.

Chronic pancreatitis with polycystic kidney disease: A rare coincidence? / Pancreatitis crónica con enfermedad renal poliquística: ¿una rara coincidencia?

INTRODUCTION: In children, chronic pancreatitis (CP) is usually associated with anatomical anomalies of the pancreas and biliary tract or is genetically determined. Autosomal dominant polycystic kidney disease (ADPKD) may present with extrarenal cyst formation, sometimes involving the pancreas. Large enough, these cysts may cause pancreatitis in ADPKD patients. Case presentation: Herein, we present a case of a 12-year-old Caucasian girl with recurrent pancreatitis with no identifiable traumatic, metabolic, infectious, drug, or immunologic causes. Structural anomalies of the pancreas, including cysts, were ruled out by imaging. However, bilateral cystic kidneys were found as an incidental finding. Her family history was negative for pancreatitis, but positive for polycystic kidney disease. Molecular analysis of ADPKD-causing mutations revealed a novel c.9659C>A (p.Ser3220*) mutation in the PKD1 gene confirming the clinical suspicion of ADPKD. Although CP may rarely occur as an extrarenal manifestation of ADPKD with pancreatic cysts, it is unusual in their absence. Thus, molecular analysis of pancreatitis susceptibility genes was performed and a homozygous pathologic c.180C>T (p.G60=) variant of the CTRC gene, known to increase the risk of CP, was confirmed. CONCLUSION: This is the first reported case of a pediatric patient with coincidence of genetically determined CP and ADPKD. Occurrence of pancreatitis in children with ADPKD without pancreatic cysts warrants further investigation of CP causing mutations

INTRODUCCIÓN: En niños, la pancreatitis crónica (CP, por sus siglas en inglés) generalmente se asocia con anomalías anatómicas del páncreas y el tracto biliar, o está genéticamente determinada. La enfermedad renal poliquística autosómica dominante (ADPKD, por sus siglas en inglés) puede presentarse con la formación de quistes extrarrenales, que a veces afecta al páncreas. Suficientemente grandes, estos quistes pueden causar pancreatitis en pacientes con ADPKD. Presentación del caso: Presentamos el caso de una niña caucásica de 12 años con pancreatitis recurrente sin causas identificables traumáticas, metabólicas, infecciosas, farmacológicas o inmunológicas. Las anomalías estructurales del páncreas, incluidos los quistes, se descartaron mediante imágenes. Sin embargo, los riñones quísticos bilaterales se encontraron como un hallazgo accidental. Su historia familiar fue negativa para la pancreatitis, pero positiva para la enfermedad renal poliquística. El análisis molecular de las mutaciones causantes de ADPKD reveló una nueva mutación c.9659C>A (p.Ser3220*) en el gen PKD1 que confirma la sospecha clínica de ADPKD. Aunque la CP rara vez ocurre como una manifestación extrarrenal de ADPKD con quistes pancreáticos es inusual. Por lo tanto, se realizó el análisis molecular de los genes de susceptibilidad a pancreatitis y se confirmó una variante homocigótica patológica c.180C>T (p.G60=) del gen CTRC, que se sabe que aumenta el riesgo de CP. CONCLUSIÓN: Este es el primer caso reportado de un paciente pediátrico con coincidencia de CP y ADPKD genéticamente determinados. La aparición de pancreatitis en niños con ADPKD sin quistes pancreáticos justifica una mayor investigación de CP que causan mutaciones

Chronic pancreatitis with polycystic kidney disease: A rare coincidence?

INTRODUCTION: In children, chronic pancreatitis (CP) is usually associated with anatomical anomalies of the pancreas and biliary tract or is genetically determined. Autosomal dominant polycystic kidney disease (ADPKD) may present with extrarenal cyst formation, sometimes involving the pancreas. Large enough, these cysts may cause pancreatitis in ADPKD patients. CASE PRESENTATION: Herein, we present a case of a 12-year-old Caucasian girl with recurrent pancreatitis with no identifiable traumatic, metabolic, infectious, drug, or immunologic causes. Structural anomalies of the pancreas, including cysts, were ruled out by imaging. However, bilateral cystic kidneys were found as an incidental finding. Her family history was negative for pancreatitis, but positive for polycystic kidney disease. Molecular analysis of ADPKD-causing mutations revealed a novel c.9659C>A (p.Ser3220*) mutation in the PKD1 gene confirming the clinical suspicion of ADPKD. Although CP may rarely occur as an extrarenal manifestation of ADPKD with pancreatic cysts, it is unusual in their absence. Thus, molecular analysis of pancreatitis susceptibility genes was performed and a homozygous pathologic c.180C>T (p.G60=) variant of the CTRC gene, known to increase the risk of CP, was confirmed. CONCLUSION: This is the first reported case of a pediatric patient with coincidence of genetically determined CP and ADPKD. Occurrence of pancreatitis in children with ADPKD without pancreatic cysts warrants further investigation of CP causing mutations.

Genetic defects in ciliary genes in autosomal dominant polycystic kidney disease.

AIM: To evaluate the genetic defects of ciliary genes causing the loss of primary cilium in autosomal dominant polycystic kidney disease (ADPKD). METHODS: We analyzed 191 structural and functional genes of the primary cilium using next-generation sequencing analysis. We analyzed the kidney samples, which were obtained from 7 patients with ADPKD who underwent nephrectomy. Each sample contained polycystic kidney tissue and matched normal kidney tissue. RESULTS: In our study, we identified genetic defects in the 5 to 15 genes in each ADPKD sample. The most frequently identified defects were found in genes encoding centrosomal proteins (PCM1, ODF2, HTT and CEP89) and kinesin family member 19 (KIF19), which are important for ciliogenesis. In addition, pathogenic mutations in the PCM1 and KIF19 genes were found in all ADPKD samples. Interestingly, mutations in the genes encoding the intraflagellar transport proteins, which are the basis of animal models of ADPKD, were only rarely detected. CONCLUSION: The results of our study revealed the actual state of structural ciliary genes in human ADPKD tissues and provided valuable indications for further research.