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.

Nance-Horan Syndrome: characterization of dental, clinical and molecular features in three new families.

BACKGROUND: Nance-Horan syndrome (NHS; MIM 302,350) is an extremely rare X-linked dominant disease characterized by ocular and dental anomalies, intellectual disability, and facial dysmorphic features. CASE PRESENTATION: We report on five affected males and three carrier females from three unrelated NHS families. In Family 1, index (P1) showing bilateral cataracts, iris heterochromia, microcornea, mild intellectual disability, and dental findings including Hutchinson incisors, supernumerary teeth, bud-shaped molars received clinical diagnosis of NHS and targeted NHS gene sequencing revealed a novel pathogenic variant, c.2416 C > T; p.(Gln806*). In Family 2, index (P2) presenting with global developmental delay, microphthalmia, cataracts, and ventricular septal defect underwent SNP array testing and a novel deletion encompassing 22 genes including the NHS gene was detected. In Family 3, two half-brothers (P3 and P4) and maternal uncle (P5) had congenital cataracts and mild to moderate intellectual deficiency. P3 also had autistic and psychobehavioral features. Dental findings included notched incisors, bud-shaped permanent molars, and supernumerary molars. Duo-WES analysis on half-brothers showed a hemizygous novel deletion, c.1867delC; p.(Gln623ArgfsTer26). CONCLUSIONS: Dental professionals can be the first-line specialists involved in the diagnosis of NHS due to its distinct dental findings. Our findings broaden the spectrum of genetic etiopathogenesis associated with NHS and aim to raise awareness among dental professionals.