GeneBe

FKRP

protein-coding

fukutin related protein

Gene summary

This gene encodes a protein which is targeted to the medial Golgi apparatus and is necessary for posttranslational modification of dystroglycan. Mutations in this gene have been associated with congenital muscular dystrophy, cognitive disability, and cerebellar cysts. Several alternatively spliced transcript variants of this gene have been described, but the full-length nature of some of these variants has not been determined. [provided by RefSeq, Oct 2008]

MANE transcript

NM_024301.5

Inheritance

AR

ClinVar variants

P:263U:487B:461

Top phenotype

Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 5; Muscular dystrophy-dystroglycanopathy (congenital with or without impaired intellectual development), type B, 5; Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 5

gnomAD constraint

pLI —, LoF o/e 0.76

Max pathogenic AF

—

Genomic locus

chr19:46,746,046-46,776,988

External References & Databases

Ensembl (ENSG00000181027)NCBI Gene (79147)OMIM (606596)HGNC:17997GenCCUniProt (Q9H9S5)AlphaFoldClinVar (FKRP)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~30.9 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

myopathy caused by variation in FKRPDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0700066

Submitter: ClinGen

*FKRP* was first reported in relation to autosomal recessive myopathy caused by variation in *FKRP* (muscular dystrophy-dystroglycanopathy included), in 2001 (Brockington et al., PMID: 11592034). At least 100 unique variants (e.g. missense, in-frame indel, nonsense, frameshift, etc.) have been reported in humans according to ClinVar and HGMD with various historical diagnoses such as Muscle-Eye-Brain Disease, Walker-Warburg Syndrome, and LGMDR9 (LGMD2I). Evidence supporting this gene-disease relationship includes case-level data and experimental data. Variants in this gene have been reported in at least 14 probands in 3 publications (PMIDs: 11592034, 11741828, 15121789). Many more probands are reported in the literature, but the maximum score for genetic evidence (12 pts) has been reached. Variants are associated with a variety of phenotypes including both congenital muscle-eye-brain or WWS or later-onset LGMD based on the residual α-Dystroglycan glycosylation activity, with higher activity correlating to a less severe presentation. The mechanism for disease is biallelic loss of function, with variants causing reduced glycosylation activity and a resulting lack of functional α-Dystroglycan. As this is an essential component in the complex responsible for stabilizing skeletal or cardiac muscle, as well as brain/eye functionality, the resulting disruption causes the presenting phenotypes such as muscle weakness, cardiac and respiratory involvement, and brain/eye abnormalities. This gene-disease association is supported by many years of experimental evidence. This includes its well-known function in the O-mannosylation of α-Dystroglycan, as well as the formation of a complex with other proteins implicated in muscular dystrophy dystroglycanopathy such as FKTN and TMEM5 and the oligomerization/activity of *FKRP* mutants being significantly less than the WT protein. There are several well-supported mouse models as well, with knock-in models of both L276I and P448L showing dystrophic features (PMIDs: 20675713, 26574668). In summary,*FKRP* is definitively associated with myopathy caused by variation in *FKRP*. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.

autosomal recessive limb-girdle muscular dystrophy type 2IDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011787

Submitter: Laboratory for Molecular Medicine

This gene-disease relationship has undergone rapid assessment. Classifications are based on preliminary review of gene-disease validity during analysis of genomic sequencing results.

congenital muscular dystrophy with intellectual disabilitySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018278

Submitter: Orphanet

muscle-eye-brain diseaseSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018939

Submitter: Orphanet

autosomal recessive limb-girdle muscular dystrophy type 2ISTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011787

Submitter: Ambry Genetics

muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0013157

Submitter: Ambry Genetics

congenital muscular dystrophy with cerebellar involvementSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018277

Submitter: Orphanet

autosomal recessive limb-girdle muscular dystrophy type 2ISUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011787

Submitter: Orphanet

muscular dystrophy-dystroglycanopathy type B5DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0011688

Submitter: Myriad Women's Health

autosomal recessive limb-girdle muscular dystrophy type 2ISTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011787

Submitter: Labcorp Genetics (formerly Invitae)

congenital muscular dystrophy without intellectual disabilitySUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018279

Submitter: Orphanet

muscular dystrophy-dystroglycanopathy, type ASUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0000171

Submitter: Orphanet

muscular dystrophy-dystroglycanopathySTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0018276

Submitter: PanelApp Australia

muscular dystrophy-dystroglycanopathy type B5STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0011688

Submitter: Labcorp Genetics (formerly Invitae)

myopathy caused by variation in FKRPDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0700066

Submitter: Natera

muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0013157

Submitter: G2P

muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0013157

Submitter: Genomics England PanelApp

Clinical Genomic Database (CGD)

Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 5; Muscular dystrophy-dystroglycanopathy (congenital with or without impaired intellectual development), type B, 5; Muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 5AR

Manifestation: Cardiovascular; Musculoskeletal; Neurologic; Ophthalmologic

Intervention: Cardiovascular

Rationale: Individuals have been described with cardiovascular complications (eg, left-ventricular dysfunction), and recognition may allow surveillance (eg, with echocardiogram) and early medical management aimed at optimizing cardiac function; Cardiac transplantation has been described

Refs: 9577386; 10838249; 11592034; 11320179; 11741828; 12707425; 14647208; 15121789; 14523375; 15580560; 16634037; 16476814; 17336067; 18060779; 18639457; 18671187; 19705481; 19917824; 20301582; 20627570Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to FKRP variants in ClinVar

38 Conditions Cataloged
Walker-Warburg congenital muscular dystrophyTotal: 909
Cardiovascular phenotypeTotal: 443
Autosomal recessive limb-girdle muscular dystrophy type 2ITotal: 324
not providedTotal: 274
Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A5Total: 175
not specifiedTotal: 125
Muscular dystrophy-dystroglycanopathy type B5Total: 120
Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A1Total: 68

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_024301.5. 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.

EffectPLPVUSLBBSum
synonymous
4
clinvar
437
clinvar
7
clinvar
 448
missense
12
clinvar
91
clinvar
475
clinvar
14
clinvar
3
clinvar
 595
nonsense
15
clinvar
35
clinvar
3
clinvar
 53
start loss
2
clinvar
1
clinvar
 3
frameshift
49
clinvar
57
clinvar
5
clinvar
 111
splice donor/acceptor (+/-2bp)
1
clinvar
 1
Total79184487451101211

Highest pathogenic variant AF is 0.001972366

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 67 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_024301.5RefSeqNP_077277.11MANE Select
ENST00000318584.10EnsemblENSP00000326570.41MANE Select
NM_001039885.3RefSeqNP_001034974.11Standard
ENST00000391909.7EnsemblENSP00000375776.21Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
fkrpDanio rerio

Structure: muscle cell

Quality: irregular spatial pattern

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Mannose type O-glycan biosynthesis - Homo sapiens (human)

Biological Process

  • protein processing
  • protein O-linked mannosylation

Molecular Function

  • dystroglycan binding
  • transferase activity

Cellular Component

  • Golgi membrane
  • extracellular space
  • nucleus
  • rough endoplasmic reticulum
  • Golgi apparatus

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000318584
Coding exons
1
Length
30943
Individuals with no LoFs
125057
Homozygous LoFs
0
Heterozygous LoFs
17
Defined
125074
p
0.0000680
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense1.852303240.7110.00002633002
Missense (PolyPhen)85124.520.682621243
Synonymous2.051261590.7930.00001361137
Loss of Function0.780911.90.7565.88e-7118

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American00.0absent
Ashkenazi Jewish00.0absent
East Asian0.000110.00011rare
Finnish0.000290.00023rare
European (Non-Finnish)0.0000760.000071rare
South Asian00.0absent
Other0.000350.00033rare

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Transferase involved in the biosynthesis of the phosphorylated O-mannosyl trisaccharide (N-acetylgalactosamine- beta-3-N-acetylglucosamine-beta-4-(phosphate-6-)mannose), a carbohydrate structure present in alpha-dystroglycan (DAG1), which is required for binding laminin G-like domain-containing extracellular proteins with high affinity. {ECO:0000269|PubMed:25279699}.;
Disease
DISEASE: Muscular dystrophy-dystroglycanopathy congenital with brain and eye anomalies A5 (MDDGA5) [MIM:613153]: An autosomal recessive disorder characterized by congenital muscular dystrophy associated with cobblestone lissencephaly and other brain anomalies, eye malformations, profound mental retardation, and death usually in the first years of life. Included diseases are the more severe Walker-Warburg syndrome and the slightly less severe muscle-eye-brain disease. {ECO:0000269|PubMed:15121789}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Muscular dystrophy-dystroglycanopathy congenital with or without mental retardation B5 (MDDGB5) [MIM:606612]: A congenital muscular dystrophy characterized by a severe phenotype with inability to walk, muscle hypertrophy, marked elevation of serum creatine kinase, secondary deficiency of laminin alpha2, and a marked reduction in alpha-dystroglycan expression. Only a subset of affected individuals have brain involvements. {ECO:0000269|PubMed:11592034, ECO:0000269|PubMed:12654965, ECO:0000269|PubMed:12666124, ECO:0000269|PubMed:14652796, ECO:0000269|PubMed:17336067}. Note=The disease is caused by mutations affecting the gene represented in this entry.; DISEASE: Muscular dystrophy-dystroglycanopathy limb-girdle C5 (MDDGC5) [MIM:607155]: An autosomal recessive degenerative myopathy with age of onset ranging from childhood to adult life, and variable severity. Clinical features include proximal muscle weakness, waddling gait, calf hypertrophy, cardiomyopathy and respiratory insufficiency. A reduction of alpha-dystroglycan and laminin alpha-2 expression can be observed on skeletal muscle biopsy from MDDGC5 patients. {ECO:0000269|PubMed:11741828, ECO:0000269|PubMed:12666124, ECO:0000269|PubMed:14523375, ECO:0000269|PubMed:14647208, ECO:0000269|PubMed:23800702}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.287

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
N
Indispensability score
0.189

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
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