NUP133

protein-coding

nucleoporin 133, the group of Minor histocompatibility antigens|Nucleoporins

Gene summary

The nuclear envelope creates distinct nuclear and cytoplasmic compartments in eukaryotic cells. It consists of two concentric membranes perforated by nuclear pores, large protein complexes that form aqueous channels to regulate the flow of macromolecules between the nucleus and the cytoplasm. These complexes are composed of at least 100 different polypeptide subunits, many of which belong to the nucleoporin family. The nucleoporin protein encoded by this gene displays evolutionarily conserved interactions with other nucleoporins. This protein, which localizes to both sides of the nuclear pore complex at interphase, remains associated with the complex during mitosis and is targeted at early stages to the reforming nuclear envelope. This protein also localizes to kinetochores of mitotic cells. [provided by RefSeq, Jul 2008]

MANE transcript

NM_018230.3

Inheritance

AR, AD

ClinVar variants

P:8U:250B:89

Top phenotype

Nephrotic syndrome, type 18; Galloway-Mowat syndrome 8

gnomAD constraint

pLI —, LoF o/e 0.31

Max pathogenic AF

—

Genomic locus

chr1:229,440,259-229,508,341

External References & Databases

Ensembl (ENSG00000069248)

Transcript & Mutation Effects

hg38 • Region Span ~68.1 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

nephrotic syndrome, type 18MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0032581

Submitter: ClinGen

The *NUP133* gene is located on chromosome 1 at q42.13 and encodes nucleoporin 133. Nucleoporin 133 is involved in poly(A)+ RNA transport and nephrogenesis (PMID:30179222). It also forms part of the Nup160 subcomplex in the nuclear pore which is composed of *NUP160*, *NUP133*, *NUP107* and *NUP96*. This complex plays a role in RNA export and in tethering *NUP98* and *NUP153* to the nucleus. It is expressed throughout the body, with disease-relevant expression noted in the kidney and brain. Multiple disease entities have been reported in association with this gene. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, there was no evidence of differences in their molecular mechanism or inheritance pattern. Therefore, the following disease entities have been lumped into one disease entity: Nephrotic syndrome, type 18 (OMIM:618177) and Galloway-Mowat syndrome 8 (OMIM: 618349). These two disease entities were lumped as part of the same spectrum of disease involving nephrotic syndrome with or without additional, extrarenal syndromic features. *NUP133* was first reported in relation to autosomal recessive nephrotic syndrome in 2018 (Braun et al., PMID: 30179222). Clinical presentation is generally characterized by nephrotic syndrome, focal segmental glomerulosclerosis, and proteinuria with or without additional neural phenotypes such as microcephaly and brain anomalies. The mechanism of pathogenicity is known to be loss of function. Six variants (missense and intronic variants leading to frameshift) have been reported in four probands in three publications (PMIDs: 30179222, 30427554, 37041680) included in this curation. A total of 3.8/12 pts. for genetic evidence was reached, considering case-level data and segregation data. This gene-disease relationship is also supported by functional studies, expression studies, in vitro assays in non-patient cells, and animal models. Morpholino knockdown of *nup133* in Xenopus embryos and *Nup133* in Zebrafish demonstrated abnormal pronephros morphology and phenocopied nephrotic syndrome respectively (PMIDs: 30179222, 30894603). Additionally, CRISPR/Cas9–mediated knockout of *NUP133* increased the formation of filopodia in immortalized human podocytes, suggesting that loss of function of *NUP133* alters the podocyte’s cytoskeleton (PMID: 30179222). Finally, *NUP133* expression was demonstrated in the brain and kidney using a TaqMan assay (PMID: 30427554) and protein interaction with *NUP107* was demonstrated by coimmunoprecipitation with the *NUP160* subcomplex (PMID: 11564755). A total of 5/6 pts. for experimental evidence was reached. In summary, there is moderate evidence supporting the relationship between *NUP133* and autosomal recessive nephrotic syndrome. This classification was approved by the ClinGen Glomerulopathy GCEP on the meeting date June 25, 2024 (SOP Version 10).

familial idiopathic steroid-resistant nephrotic syndromeSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019006

Submitter: Orphanet

nephrotic syndrome, type 18LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0032581

Submitter: Labcorp Genetics (formerly Invitae)

nephrotic syndrome, type 18STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032581

Submitter: PanelApp Australia

Galloway-Mowat syndrome 8LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0032693

Submitter: Ambry Genetics

Galloway-Mowat syndrome 8LIMITED

Inheritance Pattern: Unknown

Disease ID:MONDO:0032693

Submitter: Labcorp Genetics (formerly Invitae)

Galloway-Mowat syndrome 8STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0032693

Submitter: G2P

Galloway-Mowat syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009627

Submitter: Orphanet

nephrotic syndrome, type 18LIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0032581

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Nephrotic syndrome, type 18; Galloway-Mowat syndrome 8AR

Manifestation: Audiologic/Otolaryngologic; Craniofacial; Neurologic; Renal

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Comments: In Galloway-Mowat syndrome, renal transplantation has been described

Refs: 11793129; 30179222; 30427554

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to NUP133 variants in ClinVar

8 Conditions Cataloged

not providedTotal: 252

not specifiedTotal: 167

NUP133-related disorderTotal: 39

Nephrotic syndrome, type 18Total: 10

Galloway-Mowat syndrome 8Total: 5

Galloway-Mowat syndromeTotal: 1

focal and segmental glomerulosclerosisTotal: 1

Autosomal recessive NUP133-related disordersTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_018230.3. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			2 clinvar	68 clinvar	5 clinvar	75
missense		3 clinvar	234 clinvar	10 clinvar	6 clinvar	253
nonsense		1 clinvar	4 clinvar			5
start loss						0
frameshift		2 clinvar	1 clinvar			3
splice donor/acceptor (+/-2bp)		2 clinvar	9 clinvar			11
Total	0	8	250	78	11	347

Highest pathogenic variant AF is 0.00009160981

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 42 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_018230.3	RefSeq	NP_060700.2	26	MANE Select
ENST00000261396.6	Ensembl	ENSP00000261396.3	26	MANE Select
ENST00000851656.1	Ensembl	ENSP00000521715.1	23	Standard
ENST00000851656.2	Ensembl	ENSP00000521715.1	23	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

RNA transport - Homo sapiens (human)
tRNA processing
Disease
Signal Transduction
Gene expression (Transcription)

Biological Process

mRNA export from nucleus
protein import into nucleus
nuclear pore organization
viral process
neural tube development

Molecular Function

protein binding
structural constituent of nuclear pore

Cellular Component

condensed chromosome kinetochore
condensed chromosome outer kinetochore
nuclear envelope
nuclear pore
cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000261396
Coding exons: 26
Length: 67059
Individuals with no LoFs: 125650
Homozygous LoFs: 0
Heterozygous LoFs: 97
Defined: 125747
p: 0.000386

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.02	526	596	0.882	0.0000301	7518
Missense (PolyPhen)		243	308.77	0.787		3991
Synonymous	-0.486	230	221	1.04	0.0000112	2226
Loss of Function	5.17	20	64.9	0.308	0.00000350	772

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0023	0.0023	notable
Latino/Admixed American	0.00075	0.00072	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00033	0.00033	rare
Finnish	0.00028	0.00028	rare
European (Non-Finnish)	0.00020	0.00018	rare
South Asian	0.000033	0.000033	rare
Other	0.00016	0.00016	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Involved in poly(A)+ RNA transport. {ECO:0000269|PubMed:11684705}.;

Recessive Scores

pRec: 0.248

Intolerance Scores

LoFtool: 0.711
RVIS EVS: 0.52
RVIS percentile EVS: 80.36

Essentials

Essential (CRISPR): E
Essential (CRISPR2): E
Essential (gene trap): E
Indispensability pred.: E
Indispensability score: 0.941

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	High
Cancer	Medium	Medium	Medium