SNUPN deficiency causes a recessive muscular dystrophy due to RNA mis-splicing and ECM dysregulation.

SNURPORTIN-1, encoded by SNUPN, plays a central role in the nuclear import of spliceosomal small nuclear ribonucleoproteins. However, its physiological function remains unexplored. In this study, we investigate 18 children from 15 unrelated families who present with atypical muscular dystrophy and neurological defects. Nine hypomorphic SNUPN biallelic variants, predominantly clustered in the last coding exon, are ascertained to segregate with the disease. We demonstrate that mutant SPN1 failed to oligomerize leading to cytoplasmic aggregation in patients' primary fibroblasts and CRISPR/Cas9-mediated mutant cell lines. Additionally, mutant nuclei exhibit defective spliceosomal maturation and breakdown of Cajal bodies. Transcriptome analyses reveal splicing and mRNA expression dysregulation, particularly in sarcolemmal components, causing disruption of cytoskeletal organization in mutant cells and patient muscle tissues. Our findings establish SNUPN deficiency as the genetic etiology of a previously unrecognized subtype of muscular dystrophy and provide robust evidence of the role of SPN1 for muscle homeostasis.

Severe congenital diarrhea secondary to tufting enteropathy. case report

ABSTRACT Introduction: Tufting enteropathy is a rare cause of congenital diarrhea in neonates. It is characterized by the abnormal distribution of epithelial adhesion molecules, which causes enterocytes to shed into the lumen, forming the characteristic tufts. Case summary: A 15-day-old female neonate was taken by her parents to the emergency department of a tertiary care hospital due to diarrheal stools she had been experiencing since birth. The patient presented with dehydration, abnormal weight loss, metabolic acidosis, and acute kidney failure. She received treatment with alizapride, loperamide, zinc sulfate, and probiotics, but after 75 days of treatment she was still symptomatic. An upper tract endoscopy and colonoscopy were performed, finding flattening of the villi and lymphoid cells in the lamina propria. However, the symptoms persisted, and she died at the age of ten months. A post-mortem exome sequencing reported tufting enteropathy. Conclusions. When congenital diarrhea is present, tufting enteropathy should be considered. An early molecular study would allow to evaluate the possibility of performing an intestinal transplant or modifying the treatment to meet the patient's palliative care needs.

RESUMEN Introducción. La enteropatía en penacho es una causa rara de diarrea congénita en neonatos; esta se caracteriza por una alteración de la adhesión epitelial que ocasiona desprendimiento de enterocitos hacia el lumen y, en consecuencia, forma los característicos penachos. Se describe el caso de una paciente con esta patología. Presentación del caso. Neonata de 15 días de vida, quien fue llevada por sus padres al servicio de urgencias de un hospital de tercer nivel debido a que desde su nacimiento tuvo deposiciones diarreicas y a causa de esto presentó deshidratación, pérdida de peso, acidosis metabólica e insuficiencia renal aguda. La paciente recibió manejo con alizaprida, loperamida, sulfato de zinc y probióticos, pero a los 75 días de tratamiento continuaba sintomática. Se le practicó una endoscopia de vías digestivas y una colonoscopia que mostraron aplanamiento de las vellosidades e infiltrado de células linfoides en la lámina propia. Los síntomas continuaron y la menor falleció a los 10 meses de nacida. El resultado del exoma post mortem reportó enteropatía en penacho. Conclusiones. Ante la presencia de diarrea congénita, se debe sospechar de una enteropatía en penacho y considerar el estudio molecular temprano, pues este permite evaluar la posibilidad de realizar un trasplante intestinal o modificar el tratamiento según las necesidades de cuidado paliativo del paciente.