POGLUT1

protein-coding

protein O-glucosyltransferase 1, the group of Glycosyltransferase family 90

Gene summary

This gene encodes a protein with both O-glucosyltransferase and O-xylosyltransferase activity which localizes to the lumen of the endoplasmic reticulum. This protein has a carboxy-terminal KTEL motif which is predicted to function as an endoplasmic reticulum retention signal. This gene is an essential regulator of Notch signalling and likely plays a role in cell fate and tissue formation during development. It may also play a role in the pathogenesis of leukemia. Mutations in this gene have been associated with the autosomal dominant genodermatosis Dowling-Degos disease 4. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2014]

Previous symbols:

C3orf9
KTELC1

MANE transcript

NM_152305.3

Inheritance

AR, AD

ClinVar variants

P:30U:149B:62

Top phenotype

Dowling-Degos disease 4; Muscular dystrophy, limb-girdle, autosomal recessive 21

gnomAD constraint

pLI —, LoF o/e 0.6

Max pathogenic AF

—

Genomic locus

chr3:119,468,963-119,494,708

External References & Databases

Ensembl (ENSG00000163389)

Transcript & Mutation Effects

hg38 • Region Span ~25.7 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal recessive limb-girdle muscular dystrophy type 2R1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014977

Submitter: PanelApp Australia

autosomal recessive limb-girdle muscular dystrophyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0015152

Submitter: ClinGen

POGLUT1 was first reported in relation to autosomal recessive limb-girdle muscular dystrophy-21 (LGMDR21) in 2016 (Servián-Morilla et al., PMID: 27807076). LGMDR21 is typically characterized by young-adult onset of slowly progressive proximal upper and lower limb muscle weakness and atrophy. Additional phenotypes such as scapular winging, calf pseudohypertrophy, and contractures have been reported. A unique feature of "inside to outside" fatty degeneration has been observed in muscle biopsy in reported probands. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found a difference in inheritance pattern and phenotypic variability. Therefore, the following disease entities have been split into two separate disease entities for autosomal recessive limb-gridle muscular dystrophy-21 (OMIM: 617232) and dominant Dowling-Degos disease 4 (OMIM: 615696). Evidence supporting this gene-disease relationship includes case-level, segregation, and experimental data. Summary of Case Level Data: 10.8 POINTS. Variants in this gene have been reported in at least 9 probands in 2 publications (PMIDs: 31897643, 27807076). Variants in this gene segregated with disease in 1 additional family members in Family 1 (PMID: 31897643). Primary mechanism of disease associated is loss of function as reported in the literature (PMID: 27807076). Summary of Experimental Data: 1 POINT. This gene-disease association is also supported by functional alteration in non-human cells (PMID: 29634421). A model constructed using C2C12 cultured mouse myoblasts demonstrated that POGLUT1 knockdown reduced Notch signaling, affecting key regulators of myogenic differentiation, including PAX7 decrease and MYOD increase. The perturbed Pax7/MyoD expression balance led to a premature myogenic differentiation and an increase in myotube size. This finding was pronounced in in response to strong POGLUT1 downexpression. Considering the proposed disease mechanism for LGMD is biallelic loss-of-function leading to reduced Notch signalling that affects skeletal muscle formation and regeneration, the functional alteration evidence seems to support the gene-disease relationship. In summary, there is definitive evidence to support the relationship between POGLUT1 and autosomal recessive limb-girdle muscular dystrophy-21. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Limb-Girdle Muscular Dystrophy GCEP on the meeting date of February 8th, 2022 (SOP Version 9).

Dowling-Degos disease 4STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014307

Submitter: G2P

autosomal recessive limb-girdle muscular dystrophy type 2R1MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014977

Submitter: Ambry Genetics

Dowling-Degos disease 4MODERATE

Inheritance Pattern: AD

Disease ID:MONDO:0014307

Submitter: Ambry Genetics

Dowling-Degos diseaseSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0008371

Submitter: Orphanet

Dowling-Degos disease 4STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014307

Submitter: PanelApp Australia

autosomal recessive limb-girdle muscular dystrophy type 2R1SUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0014977

Submitter: Orphanet

Dowling-Degos disease 4STRONG

Inheritance Pattern: AD

Disease ID:MONDO:0014307

Submitter: Labcorp Genetics (formerly Invitae)

autosomal recessive limb-girdle muscular dystrophy type 2R1STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014977

Submitter: Labcorp Genetics (formerly Invitae)

Clinical Genomic Database (CGD)

Dowling-Degos disease 4; Muscular dystrophy, limb-girdle, autosomal recessive 21AD/AR

Manifestation: Dermatologic; Musculoskeletal

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

Refs: 21971768; 24387993; 27807076

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to POGLUT1 variants in ClinVar

6 Conditions Cataloged

not providedTotal: 274

Inborn genetic diseasesTotal: 57

not specifiedTotal: 13

Autosomal recessive limb-girdle muscular dystrophy type 2R1Total: 12

POGLUT1-related disorderTotal: 9

Dowling-Degos disease 4Total: 6

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_152305.3. 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			1 clinvar	51 clinvar	3 clinvar	55
missense	2 clinvar	4 clinvar	141 clinvar	8 clinvar		155
nonsense	2 clinvar	8 clinvar				10
start loss						0
frameshift	9 clinvar		2 clinvar			11
splice donor/acceptor (+/-2bp)	1 clinvar	4 clinvar	5 clinvar			10
Total	14	16	149	59	3	241

Highest pathogenic variant AF is 0.000044608838

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 53 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_152305.3	RefSeq	NP_689518.1	11	MANE Select
ENST00000295588.9	Ensembl	ENSP00000295588.4	11	MANE Select
ENST00000460339.1	Ensembl	ENSP00000420594.1	3	Standard
ENST00000476573.5	Ensembl	ENSP00000419865.1	6	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Other types of O-glycan biosynthesis - Homo sapiens (human)
Signal Transduction
Pre-NOTCH Processing in the Endoplasmic Reticulum
Pre-NOTCH Expression and Processing
Signaling by NOTCH

Biological Process

somitogenesis
protein O-linked glycosylation
gastrulation
regulation of gastrulation
protein O-linked glycosylation via serine

Molecular Function

protein xylosyltransferase activity
UDP-glucosyltransferase activity
UDP-xylosyltransferase activity
glucosyltransferase activity

Cellular Component

endoplasmic reticulum lumen

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000295588
Coding exons: 11
Length: 25771
Individuals with no LoFs: 125706
Homozygous LoFs: 0
Heterozygous LoFs: 42
Defined: 125748
p: 0.000167

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.15	164	211	0.777	0.0000107	2570
Missense (PolyPhen)		58	82.609	0.70211		963
Synonymous	-0.834	81	72.0	1.13	0.00000342	703
Loss of Function	2.00	17	28.6	0.595	0.00000165	297

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00037	0.00037	rare
Latino/Admixed American	0.00026	0.00026	rare
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0.00011	0.00011	rare
Finnish	0.000056	0.000046	rare
European (Non-Finnish)	0.00017	0.00017	rare
South Asian	0.000099	0.000098	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Dual specificity glycosyltransferase that catalyzes the transfer of glucose and xylose from UDP-glucose and UDP-xylose, respectively, to a serine residue found in the consensus sequence of C-X-S-X-P-C (PubMed:21081508, PubMed:21490058, PubMed:21949356, PubMed:27807076, PubMed:28775322). Specifically targets extracellular EGF repeats of protein such as CRB2, F7, F9 and NOTCH2 (PubMed:21081508, PubMed:21490058, PubMed:21949356, PubMed:27807076, PubMed:28775322). Acts as a positive regulator of Notch signaling by mediating O-glucosylation of Notch, leading to regulate muscle development (PubMed:27807076). Notch glucosylation does not affect Notch ligand binding (PubMed:21490058). Required during early development to promote gastrulation: acts by mediating O-glucosylation of CRB2, which is required for CRB2 localization to the cell membrane (By similarity). {ECO:0000250|UniProtKB:Q8BYB9, ECO:0000269|PubMed:21081508, ECO:0000269|PubMed:21490058, ECO:0000269|PubMed:21949356, ECO:0000269|PubMed:27807076, ECO:0000269|PubMed:28775322}.;
Disease: DISEASE: Limb-girdle muscular dystrophy 2Z (LGMD2Z) [MIM:617232]: A form of autosomal recessive limb-girdle muscular dystrophy, a degenerative myopathy characterized by slowly progressive wasting and weakness of the proximal muscles of arms and legs around the pelvic or shoulder girdles, elevated creatine kinase levels and dystrophic features on muscle biopsy. LGMD2Z is characterized by young-adult onset. {ECO:0000269|PubMed:27807076}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.107

Intolerance Scores

RVIS EVS: 0.04
RVIS percentile EVS: 56.92

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.114

Gene Damage Prediction

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