autosomal recessive limb-girdle muscular dystrophy type 2U

Summary

autosomal recessive limb-girdle muscular dystrophy type 2U (MONDO:0014474) is a disease with 3 cohort genes and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 3
• ClinVar variants: 441
• Phenotypes (HPO): 16
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		8	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

16 HPO clinical features (Orphanet curated; top 16 by frequency):

HPO ID	Term	Frequency
HP:0003325	Limb-girdle muscle weakness	Very frequent (80-99%)
HP:0030046	Hypoglycosylation of alpha-dystroglycan	Very frequent (80-99%)
HP:0000158	Macroglossia	Frequent (30-79%)
HP:0001626	Abnormality of the cardiovascular system	Frequent (30-79%)
HP:0002792	Reduced vital capacity	Frequent (30-79%)
HP:0003202	Skeletal muscle atrophy	Frequent (30-79%)
HP:0003707	Calf muscle pseudohypertrophy	Frequent (30-79%)
HP:0008994	Proximal muscle weakness in lower limbs	Frequent (30-79%)
HP:0008997	Proximal muscle weakness in upper limbs	Frequent (30-79%)
HP:0030234	Highly elevated creatine kinase	Frequent (30-79%)
HP:0002505	Loss of ambulation	Occasional (5-29%)
HP:0003326	Myalgia	Occasional (5-29%)
HP:0003691	Scapular winging	Occasional (5-29%)
HP:0008305	Exercise-induced myoglobinuria	Occasional (5-29%)
HP:0000478	Abnormality of the eye	Very rare (<1-4%)
HP:0011446	Abnormality of higher mental function	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal recessive limb-girdle muscular dystrophy type 2U
Mondo ID	MONDO:0014474
OMIM	616052
Orphanet	352479
DOID	DOID:0110295
UMLS	C5190987
MedGen	1683417
GARD	0017519
Is cancer (heuristic)	no

Also known as: autosomal recessive limb-girdle muscular dystrophy caused by mutation in ISPD · ISPD autosomal recessive limb-girdle muscular dystrophy · LGMD2U · MDDGC7 · muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 7

Data availability: 441 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › congenital nervous system disorder › congenital muscular dystrophy › muscular dystrophy-dystroglycanopathy › muscular dystrophy-dystroglycanopathy, type C › autosomal recessive limb-girdle muscular dystrophy type 2U

Related subtypes (8): autosomal recessive limb-girdle muscular dystrophy type 2K, autosomal recessive limb-girdle muscular dystrophy type 2M, autosomal recessive limb-girdle muscular dystrophy type 2O, autosomal recessive limb-girdle muscular dystrophy type 2N, autosomal recessive limb-girdle muscular dystrophy type 2P, autosomal recessive limb-girdle muscular dystrophy type 2T, limb-girdle muscular dystrophy due to POMK deficiency, muscular dystrophy-dystroglycanopathy (limb-girdle), type C, 8

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

441 retrieved; paginated sample, class counts are floors:

172 uncertain significance, 136 likely benign, 50 conflicting classifications of pathogenicity, 47 pathogenic, 11 benign, 10 likely pathogenic, 9 benign/likely benign, 6 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1072533	NC_000007.13:g.(?16445666)(16445982_?)del	CRPPA	Pathogenic	criteria provided, single submitter
1072534	NC_000007.13:g.(?16131310)(16255832_?)del	CRPPA	Pathogenic	criteria provided, single submitter
1076250	NM_001101426.4(CRPPA):c.550C>T (p.Arg184Ter)	CRPPA	Pathogenic	criteria provided, multiple submitters, no conflicts
1342054	NM_001101426.4(CRPPA):c.54_55delinsTGC (p.Ser19fs)	CRPPA	Pathogenic	criteria provided, multiple submitters, no conflicts
156454	NM_001101426.4(CRPPA):c.161G>C (p.Gly54Ala)	CRPPA	Pathogenic	no assertion criteria provided
156455	NM_001101426.4(CRPPA):c.1105GTT[3] (p.Val372del)	CRPPA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1680626	NC_000007.13:g.(?16341026)(16341111_?)del	CRPPA	Pathogenic	criteria provided, single submitter
1680627	NC_000007.13:g.(?16341026)(16415886_?)del	CRPPA	Pathogenic	criteria provided, single submitter
1680628	NC_000007.13:g.(?16348128)(16445982_?)del	CRPPA	Pathogenic	criteria provided, single submitter
1680630	NC_000007.13:g.(?16460671)(16460947_?)del	CRPPA	Pathogenic	criteria provided, single submitter
1983342	NM_001101426.4(CRPPA):c.79_80del (p.Thr27fs)	CRPPA	Pathogenic	criteria provided, single submitter
2070304	NM_001101426.4(CRPPA):c.17_24dup (p.Ala9fs)	CRPPA	Pathogenic	criteria provided, single submitter
2078955	NM_001101426.4(CRPPA):c.534+1del	CRPPA	Pathogenic	criteria provided, single submitter
2122850	NM_001101426.4(CRPPA):c.1092C>A (p.Cys364Ter)	CRPPA	Pathogenic	criteria provided, single submitter
2142758	NM_001101426.4(CRPPA):c.1137dup (p.Lys380Ter)	CRPPA	Pathogenic	criteria provided, single submitter
2423709	NC_000007.13:g.(?16415697)(16460947_?)del	CRPPA	Pathogenic	criteria provided, single submitter
2423710	NC_000007.13:g.(?16297995)(16317871_?)del	CRPPA	Pathogenic	criteria provided, single submitter
2423714	NC_000007.13:g.(?16131320)(16460947_?)del	CRPPA	Pathogenic	criteria provided, single submitter
2423715	NC_000007.13:g.(?16131320)(16255842_?)del	CRPPA	Pathogenic	criteria provided, single submitter
279985	NM_001101426.4(CRPPA):c.53dup (p.Ser19Glufs)	CRPPA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
282846	NM_001101426.4(CRPPA):c.643C>T (p.Gln215Ter)	CRPPA	Pathogenic	criteria provided, multiple submitters, no conflicts
287941	NM_001101426.4(CRPPA):c.258-1G>C	CRPPA	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2924564	NM_001101426.4(CRPPA):c.896del (p.Gly299fs)	CRPPA	Pathogenic	criteria provided, single submitter
2930168	NM_001101426.4(CRPPA):c.337C>T (p.Gln113Ter)	CRPPA	Pathogenic	criteria provided, single submitter
2941204	NM_001101426.4(CRPPA):c.6_13dup (p.Pro5fs)	CRPPA	Pathogenic	criteria provided, single submitter
31561	NM_001101426.4(CRPPA):c.1120-1G>T	CRPPA	Pathogenic	criteria provided, multiple submitters, no conflicts
31568	NM_001101426.4(CRPPA):c.802C>T (p.Arg268Ter)	CRPPA	Pathogenic	criteria provided, multiple submitters, no conflicts
3245803	NC_000007.13:g.(?16317734)(16317871_?)del	CRPPA	Pathogenic	criteria provided, single submitter
3245804	NC_000007.13:g.(?16297995)(16415886_?)del	CRPPA	Pathogenic	criteria provided, single submitter
3245805	NC_000007.13:g.(?16297995)(16348272_?)del	CRPPA	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 4 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
CRPPA	Definitive	Autosomal recessive	muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 7	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CRPPA	Orphanet:352479	ISPD-related limb-girdle muscular dystrophy R20
CRPPA	Orphanet:370980	Congenital muscular dystrophy without intellectual disability
CRPPA	Orphanet:588	Muscle-eye-brain disease
CRPPA	Orphanet:899	Walker-Warburg syndrome

Cohort genes → proteins

3 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CRPPA	HGNC:37276	ENSG00000214960	A4D126	D-ribitol-5-phosphate cytidylyltransferase	gencc,clinvar
LRRC72	HGNC:42972	ENSG00000205858	A6NJI9	Leucine-rich repeat-containing protein 72	clinvar
CRPPA-AS1	HGNC:48962	ENSG00000229688		CRPPA antisense RNA 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CRPPA	D-ribitol-5-phosphate cytidylyltransferase	Cytidylyltransferase required for protein O-linked mannosylation.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 2 · Druggable fraction: 0.33

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Enzyme (other)	1	4.0×	0.460
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CRPPA	Enzyme (other)	yes	2.7.7.40	ISPD_synthase_CS, Nucleotide-diphossugar_trans, IspD/TarI
LRRC72	Other/Unknown	no		Leu-rich_rpt, LRR_dom_sf, LRC72
CRPPA-AS1	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

2 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
male germ line stem cell (sensu Vertebrata) in testis	3
left testis	2
calcaneal tendon	1
corpus callosum	1
right testis	1
sperm	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CRPPA	134	ubiquitous	yes	corpus callosum, male germ line stem cell (sensu Vertebrata) in testis, calcaneal tendon
LRRC72	21	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, left testis, right testis
CRPPA-AS1	147	tissue_specific	marker	sperm, male germ line stem cell (sensu Vertebrata) in testis, left testis

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CRPPA	1,629
LRRC72	370
CRPPA-AS1	0

Intra-cohort edges

A	B	Sources
CRPPA	LRRC72	string_interaction

Structural data

PDB: 1 · AlphaFold-only: 1 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CRPPA	A4D126	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
LRRC72	A6NJI9	79.40

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 3 evidence-associated genes (1 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Matriglycan biosynthesis on DAG1	1	815.7×	0.001	CRPPA

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
isoprenoid biosynthetic process	1	1685.2×	0.002	CRPPA
protein O-linked glycosylation via mannose	1	936.2×	0.002	CRPPA
axon guidance	1	90.6×	0.011	CRPPA

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 3

Druggability breadth: 0 of 3 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CRPPA	0	0
LRRC72	0	0
CRPPA-AS1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
CRPPA	2.7.7.40	D-ribitol-5-phosphate cytidylyltransferase

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	CRPPA
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	LRRC72, CRPPA-AS1

Undrugged target profiles

3 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
CRPPA	0	—
LRRC72	0	—
CRPPA-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05989620	Not specified	RECRUITING	Long-Term Development of Muscular Dystrophy Outcome Assessments