Novel biallelicNUP107variants affect the nuclear pore complex and expand the clinical spectrum to include brain malformations DOI

Loisa Dana Bonde,

Laura Hecher,

Malik Alawi

и другие.

Journal of Medical Genetics, Год журнала: 2025, Номер unknown, С. jmg - 110671

Опубликована: Май 11, 2025

Biallelic variants in NUP107 cause isolated or syndromic steroid-resistant nephrotic syndrome (SRNS), characterised by proteinuria, hypoalbuminaemia and focal segmental glomerulosclerosis that progresses to end-stage renal disease. Patients with SRNS have microcephaly, developmental delay intellectual disability short stature. Simplified gyration is observed some individuals. We report on a 2-year-old girl novel biallelic variants, c.2606G>T; p.(Gly869Val) c.1576+1G>A, proteinuria severe neurodevelopmental disorder delay, early-onset seizures, sensorineural hearing loss brain structural anomalies, including simplified gyral pattern hypoplasia of the corpus callosum, pons, brainstem cerebellum. part NUP107-160 complex, which, together other proteins termed nucleoporins, forms nuclear pore complex (NPC). The NPC regulates nucleocytoplasmic transport cellular processes. In patient-derived fibroblasts, we identified aberrantly spliced mRNAs frameshift premature stop codon leading non-sense-mediated mRNA decay, reduced levels transcripts, NUP133 proteins, number. addition, an abnormal nucleolar morphology was found cells. Our functional data support conclusion underlie patient’s phenotype, thereby broadening clinical spectrum associated include development.

Язык: Английский

A Novel NUP85 Variant Expanding the Phenotypic Spectrum of NUP85‐Associated Steroid‐Resistant Nephrotic Syndrome DOI Open Access
Eda Didem Kurt Şükür, Emel Timuçin, Turgut Baştuğ

и другие.

Clinical Genetics, Год журнала: 2025, Номер unknown

Опубликована: Фев. 13, 2025

Steroid-resistant nephrotic syndrome (SRNS) is a severe kidney disorder linked to over 60 genes, including NUP85, which plays key role in nuclear pore function and glomerulogenesis. We identified novel homozygous NUP85 variant (NM_024844.5: c.1379G > A, p.Arg460Gln) pediatric SRNS patient who also presented with cleft lip-palate mild intellectual disability, marking the first reported association of these phenotypes variant. Molecular dynamics simulations revealed that destabilizes protein's helix bundle, providing mechanistic insights into its potential pathogenic effects. This study broadens known phenotypic spectrum NUP85-related conditions highlights value computational tools, such as molecular dynamics, unraveling impact variants.

Язык: Английский

Процитировано

1
Genetic and clinical spectrum of steroid-resistant nephrotic syndrome with nuclear pore gene mutation DOI
H.J. Yang,

Gaohong Zhu,

Wenjun Shao

и другие.

Pediatric Nephrology, Год журнала: 2025, Номер unknown

Опубликована: Янв. 16, 2025

Язык: Английский

Процитировано

0
Loss of Nup160 dysregulates Cdc42 in the podocytes of podocyte-specific Nup160 knockout mice DOI

Deying Liu,

Jiaxin Li,

Chan Xu

и другие.

Human Molecular Genetics, Год журнала: 2025, Номер unknown

Опубликована: Апрель 29, 2025

Abstract Mutations in four genes encoding the outer ring complex of nuclear pore complexes (NPCs), NUP85, NUP107, NUP133 and NUP160, cause monogenic steroid-resistant nephrotic syndrome (SRNS). Knockout or immortalized human podocytes activates CDC42, an important effector SRNS pathogenesis. However, it is unknown whether not loss NUP160 dysregulates CDC42 podocytes. Here, we generated a podocyte-specific Nup160 knockout mouse model with double-fluorescent (mT/mG) Cre reporter using CRISPR/Cas9 Cre/loxP technologies. We investigated syndrome-associated phenotypes Nup160podo−/− mice, performed single-cell transcriptomic proteomic analysis glomerular suspension cells cultured primary podocytes, respectively. The mice exhibited progressive proteinuria fusion podocyte foot processes. found decreased Cdc42 protein normal transcriptional level transcriptomes proteomes. subsequently observed that both kidney tissues although mRNA levels were elevated mice. also activity was significantly reduced In conclusion, dysregulated Our findings suggest dysregulation may contribute to pathogenesis patients mutations NUP160.

Язык: Английский

Процитировано

0
Novel biallelicNUP107variants affect the nuclear pore complex and expand the clinical spectrum to include brain malformations DOI

Loisa Dana Bonde,

Laura Hecher,

Malik Alawi

и другие.

Journal of Medical Genetics, Год журнала: 2025, Номер unknown, С. jmg - 110671

Опубликована: Май 11, 2025

Biallelic variants in NUP107 cause isolated or syndromic steroid-resistant nephrotic syndrome (SRNS), characterised by proteinuria, hypoalbuminaemia and focal segmental glomerulosclerosis that progresses to end-stage renal disease. Patients with SRNS have microcephaly, developmental delay intellectual disability short stature. Simplified gyration is observed some individuals. We report on a 2-year-old girl novel biallelic variants, c.2606G>T; p.(Gly869Val) c.1576+1G>A, proteinuria severe neurodevelopmental disorder delay, early-onset seizures, sensorineural hearing loss brain structural anomalies, including simplified gyral pattern hypoplasia of the corpus callosum, pons, brainstem cerebellum. part NUP107-160 complex, which, together other proteins termed nucleoporins, forms nuclear pore complex (NPC). The NPC regulates nucleocytoplasmic transport cellular processes. In patient-derived fibroblasts, we identified aberrantly spliced mRNAs frameshift premature stop codon leading non-sense-mediated mRNA decay, reduced levels transcripts, NUP133 proteins, number. addition, an abnormal nucleolar morphology was found cells. Our functional data support conclusion underlie patient’s phenotype, thereby broadening clinical spectrum associated include development.

Язык: Английский

Процитировано

0