EPB41

Summary

EPB41 (erythrocyte membrane protein band 4.1, HGNC:3377) is a protein-coding gene on chromosome 1p35.3, encoding Protein 4.1 (P11171). Protein 4.1 is a major structural element of the erythrocyte membrane skeleton.

The protein encoded by this gene, together with spectrin and actin, constitute the red cell membrane cytoskeletal network. This complex plays a critical role in erythrocyte shape and deformability. Mutations in this gene are associated with type 1 elliptocytosis (EL1). Alternatively spliced transcript variants encoding different isoforms have been described for this gene.

Source: NCBI Gene 2035 — RefSeq curated summary.

At a glance

• Gene–disease (curated): elliptocytosis 1 (Definitive, GenCC) — +1 more curated relationship
• GWAS associations: 15
• Clinical variants (ClinVar): 303 total — 17 pathogenic, 17 likely-pathogenic
• Phenotypes (HPO): 26
• Druggable target: yes
• MANE Select transcript: NM_001376013

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:3377
Approved symbol	EPB41
Name	erythrocyte membrane protein band 4.1
Location	1p35.3
Locus type	gene with protein product
Status	Approved
Aliases	4.1R
Ensembl gene	ENSG00000159023
Ensembl biotype	protein_coding
OMIM	130500
Entrez	2035

Gene structure

Transcript identifiers

Ensembl transcripts: 88 — 72 protein_coding, 6 retained_intron, 6 protein_coding_CDS_not_defined, 4 nonsense_mediated_decay

ENST00000343067, ENST00000347529, ENST00000349460, ENST00000373797, ENST00000373798, ENST00000373800, ENST00000460378, ENST00000462032, ENST00000482464, ENST00000488277, ENST00000490308, ENST00000636666, ENST00000642643, ENST00000642937, ENST00000643155, ENST00000643173, ENST00000643302, ENST00000643604, ENST00000644342, ENST00000644470, ENST00000644600, ENST00000644780, ENST00000644848, ENST00000645111, ENST00000645184, ENST00000645999, ENST00000646189, ENST00000646260, ENST00000646800, ENST00000646871, ENST00000647103, ENST00000647918, ENST00000648181, ENST00000648891, ENST00000649674, ENST00000649717, ENST00000649992, ENST00000650132, ENST00000650265, ENST00000706361, ENST00000870250, ENST00000870251, ENST00000870252, ENST00000870253, ENST00000870254, ENST00000870255, ENST00000870256, ENST00000921693, ENST00000921694, ENST00000921695, ENST00000921696, ENST00000921697, ENST00000921698, ENST00000921699, ENST00000921700, ENST00000921701, ENST00000921702, ENST00000921703, ENST00000921704, ENST00000921705, ENST00000921706, ENST00000921707, ENST00000921708, ENST00000921709, ENST00000921710, ENST00000921711, ENST00000921712, ENST00000921713, ENST00000921714, ENST00000921715, ENST00000921716, ENST00000921717, ENST00000921718, ENST00000921719, ENST00000921720, ENST00000921721, ENST00000921722, ENST00000921723, ENST00000921724, ENST00000921725, ENST00000921726, ENST00000921727, ENST00000921728, ENST00000921729, ENST00000921730, ENST00000921731, ENST00000921732, ENST00000921733

RefSeq mRNA: 22 — MANE Select: NM_001376013 NM_001166005, NM_001166006, NM_001166007, NM_001376013, NM_001376014, NM_001376015, NM_001376016, NM_001376017, NM_001376018, NM_001376019, NM_001376020, NM_001376021, NM_001376022, NM_001376023, NM_001376024, NM_001376025, NM_001376026, NM_001376027, NM_001376028, NM_004437, NM_203342, NM_203343

CCDS: CCDS330, CCDS331, CCDS53288, CCDS53289, CCDS85947, CCDS90897, CCDS90898, CCDS90899, CCDS90900, CCDS90901, CCDS90902

Canonical transcript exons

ENST00000343067 — 21 exons

Exon	Start	End
ENSE00001065024	29035826	29035923
ENSE00001065025	29033093	29033245
ENSE00001065026	28997215	28997319
ENSE00001065027	29018224	29018442
ENSE00001065029	29060422	29060484
ENSE00001065030	29015692	29015767
ENSE00001065031	29053104	29053312
ENSE00001065032	29011865	29011907
ENSE00001065035	29039254	29039426
ENSE00001065038	29058811	29058852
ENSE00001065039	29058589	29058645
ENSE00001065043	29030400	29030487
ENSE00003461752	29064982	29065158
ENSE00003487555	29097807	29097935
ENSE00003493439	29112368	29112448
ENSE00003507583	28993330	28993542
ENSE00003509531	29109336	29109437
ENSE00003538414	29115699	29115803
ENSE00003686609	28987431	28987905
ENSE00003823103	28914569	28914768
ENSE00003825110	29116819	29120041

Expression profiles

Bgee: expression breadth ubiquitous, 261 present calls, max score 99.17.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 39.5928 / max 2597.6035, expressed in 1716 samples.

FANTOM5 promoters (8 alternative TSS)

Promoter ID	TPM avg	Samples expressed
1843	23.9157	1622
1845	7.0381	876
1847	5.1241	700
1844	1.9748	356
1846	0.5189	250
1849	0.4395	208
1848	0.3206	167
1852	0.2612	78

Top tissues by expression

286 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
trabecular bone tissue	UBERON:0002483	99.17	gold quality
cerebellar hemisphere	UBERON:0002245	97.79	gold quality
cerebellar cortex	UBERON:0002129	97.75	gold quality
right hemisphere of cerebellum	UBERON:0014890	97.26	gold quality
colonic epithelium	UBERON:0000397	96.36	gold quality
cerebellum	UBERON:0002037	96.06	gold quality
esophagus squamous epithelium	UBERON:0006920	94.98	gold quality
tonsil	UBERON:0002372	94.78	gold quality
blood	UBERON:0000178	94.77	gold quality
amniotic fluid	UBERON:0000173	94.06	gold quality
epithelium of nasopharynx	UBERON:0001951	93.82	gold quality
monocyte	CL:0000576	93.17	gold quality
bone marrow	UBERON:0002371	93.06	gold quality
granulocyte	CL:0000094	93.01	gold quality
mucosa of sigmoid colon	UBERON:0004993	92.64	gold quality
leukocyte	CL:0000738	92.51	gold quality
lymph node	UBERON:0000029	92.49	gold quality
colonic mucosa	UBERON:0000317	92.48	gold quality
gingival epithelium	UBERON:0001949	92.39	gold quality
upper leg skin	UBERON:0004262	92.27	gold quality
mononuclear cell	CL:0000842	92.18	gold quality
cardia of stomach	UBERON:0001162	91.72	gold quality
pylorus	UBERON:0001166	91.66	gold quality
gingiva	UBERON:0001828	91.46	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	91.26	gold quality
jejunal mucosa	UBERON:0000399	91.17	gold quality
ganglionic eminence	UBERON:0004023	90.49	gold quality
buccal mucosa cell	CL:0002336	90.48	gold quality
ventricular zone	UBERON:0003053	90.44	gold quality
cerebellar vermis	UBERON:0004720	90.40	gold quality

Single-cell (SCXA)

Detected in 7 experiment(s), a significant marker in 6.

Experiment	Marker?	Max mean expression
E-MTAB-11121	yes	1213.15
E-MTAB-9221	yes	11.68
E-HCAD-5	yes	9.58
E-MTAB-6678	yes	4.41
E-CURD-112	yes	3.82
E-MTAB-10042	no	401.36
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): HOXA7, ZNF148

miRNA regulators (miRDB)

129 targeting EPB41, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-30E-5P	100.00	76.32	3242
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-4481	100.00	66.42	1669
HSA-MIR-6748-5P	100.00	65.81	1057
HSA-MIR-30A-5P	100.00	76.31	3233
HSA-MIR-30B-5P	100.00	76.29	3248
HSA-MIR-30C-5P	100.00	76.29	3248
HSA-MIR-30D-5P	100.00	76.32	3233
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-4425	100.00	67.59	1049
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-4692	100.00	67.32	2066
HSA-MIR-371B-5P	99.99	75.34	4759
HSA-MIR-6759-5P	99.99	66.54	785
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-373-5P	99.98	75.36	4753
HSA-MIR-616-5P	99.98	75.58	4775
HSA-MIR-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-4745-5P	99.98	65.95	1028
HSA-MIR-6793-5P	99.97	65.95	758
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-381-3P	99.93	71.87	2854
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-4493	99.90	66.48	977

Literature-anchored findings (GeneRIF, showing 40)

• Reassignment of the EPB4.1 gene to 1p36 and assessment of its involvement in neuroblastomas. (PMID:11737230)
• With deletions or mutations, the ability of the 8 amino acid motif (LKKNFMES) of the spectrin-actin-binding domain of erythrocyte protein 4.1 recombinant peptides to form ternary complexes with spectrin and actin is remarkably diminished. (PMID:12044158)
• falcipain-2-mediated cleavage of protein 4.1 occurs immediately after lysine 437, which lies within a region of the spectrin-actin-binding domain critical for erythrocyte membrane stability. (PMID:12130521)
• A splicing alteration of pre-mRNA generates 2 protein isoforms with distinct assembly to spindle poles in mitotic cells (PMID:12239178)
• A 4.1R isoform expressing the leucine-rich sequence binds to the export receptor CRM1 in a RanGTP-dependent fashion, whereas this does not occur in a mutant whose two conserved hydrophobic residues are substituted (PMID:12427749)
• synthesis of structurally distinct 4.1R protein isoforms in various cell types is regulated by a novel mechanism requiring coordination between upstream transcription initiation events and downstream alternative splicing events (PMID:12522012)
• A novel member of the protein 4.1 family was cloned; it has focal expression in the ovary. (PMID:12601556)
• protein 4.1R has a role in recruiting hDlg to the lateral membrane in epithelial cells (PMID:12807908)
• Protein 4.1R functions as an important tumor suppressor in the molecular pathogenesis of meningioma (PMID:12901833)
• interaction with nuclear actin during nuclear assembly in vitro (PMID:12960380)
• alpha-spectrin ubiquitination at repeats 20 and 21 increases the dissociation of the spectrin-protein-4.1-actin ternary complex thereby regulating protein 4.1’s ability to stimulate the spectrin-actin interaction (PMID:15040429)
• 135-kDa non-erythroid 4.1R has a role in cell division (PMID:15184364)
• protein 4.1R mitotic regulation involves phosphorylation by cdc2 kinase (PMID:15525677)
• 4.1R plays a key role at the centrosome, contributing to the maintenance of a radial microtubule organization (PMID:15564380)
• protein 4.1 phosphorylation modulates erythrocyte membrane mechanical function (PMID:15611095)
• Alternative splicing isoforms are present in muscular dystsrophy skeletal muscle. (PMID:15714879)
• 4.1R loss of expression was statistically more common in ependymomas. (PMID:15731777)
• We speculate that over the repetitive cycles of heart muscle contraction and relaxation, 4.1s are likely to locate, support, and coordinate functioning of key membrane-bound macromolecular assemblies. (PMID:15834631)
• 4.1R binds to the separate calponin homology CH1 and CH2 domains of beta I spectrin. (PMID:16060676)
• EPB41 gene expression was unchanged in all analyzed meningiomas. This suggests that involvement of the EPB41 gene (4.1R protein) in meningioma pathogenesis should be reconsidered. (PMID:16157202)
• interaction of protein 4.1 with TRPC4 is required for activation of the endothelial ISOC channel. (PMID:16254212)
• protein 4.1R interactions with membrane proteins are regulated by Ca2+ and calmodulin [review] (PMID:16368534)
• Fox-1 and Fox-2 splicing factors have roles in alternative splicing of protein 4.1R (PMID:16537540)
• 4.1R60 isoforms are constitutively self-associated, whereas 4.1R80 and 4.1R135 self-association is prevented by intramolecular interactions. (PMID:16881872)
• The interaction of Plasmodium falciparum EBA-181 with the highly conserved 10 kDa domain of 4.1R provides new insight into the molecular mechanisms utilized by P. falciparum during erythrocyte entry (PMID:17087826)
• A decreased expression pattern of the 4.1R protein was observed in the erythrocytes from patients with atypical NA. (PMID:17298666)
• A regulated splicing event in protein 4.1R pre-mRNA-the inclusion of exon 16-encoding peptides for spectrin-actin binding-occurs in late erythroid differentiation (PMID:17715393)
• A deficit in protein 4.1R is recurrent in myeloid malignancies and should be particularly investigated when deletion del (20 q) is present, since this chromosomal abnormality was present in four out of six patients. (PMID:17994571)
• In the 4.1R gene, intrasplicing ultimately determines N-terminal protein structure and function. (PMID:18079699)
• 4.1R makes crucial contributions to the structural integrity of centrosomes & mitotic spindles which normally enable mitosis and anaphase to proceed with coordinated precision. (PMID:18212055)
• Findings enable us to offer potential new insights into the differential contribution of 4.1R isoforms, 4.1R(80) and 4.1R(135), to membrane assembly during terminal erythroid differentiation. (PMID:18691159)
• p55 binds to two distinct sites within the FERM domain, and the alternatively spliced exon 5 is necessary for the membrane targeting of protein 4.1R in epithelial cells. (PMID:18952129)
• Study reports the first NMR-derived structure of the 4.1R FERM alpha-lobe domain and propose a new glycophorin C-binding site on the 4.1R FERM alpha-lobe domain, based on our NMR experiments. (PMID:19338061)
• Proteins in the membrane skeleton protein 4.1 family are weakly expressed in non-small cell lung cancer and are related to tumor cell differentiation. (PMID:19624891)
• 4.1R gene expression involves transcriptional regulation coupled with a complex splicing regulatory network. (PMID:19729518)
• 4.1R plays a role in the phosphatidylserine exposure signaling pathway that is of fundamental importance in red cell turnover. (PMID:19794081)
• Data suggest that one or both of proteins 4.1 and 4.2 cause a portion of band 3 to localize near the spectrin-actin junctions and provide another point of attachment between the membrane skeleton and the lipid bilayer. (PMID:20007969)
• Four EPB41 SNPs showed allelic and genotypic associations with MP in first stage. In the second stage, the allele rs4654388 showed the strongest significant association with MP. rs4654388 G-allele was associated with a significantly increased risk of MP. (PMID:20797695)
• in addition to two known minor shortened and stable spliceoforms, a 4.1R splicing mutation activates an intronic cryptic splice site, which results in a nonsense mRNA major isoform, targeted to degradation in intact cells by Nonsense-mediated mRNA decay. (PMID:20863723)
• Data provide evidence that 4.1R has functional interactions with emerin and A-type lamin that impact upon nuclear architecture, centrosome-nuclear envelope association and the regulation of beta-catenin transcriptional co-activator activity. (PMID:21486941)

Cross-species orthologs

10 orthologs

Organism	Symbol	Gene ID
danio_rerio	epb41a	ENSDARG00000099283
mus_musculus	Epb41	ENSMUSG00000028906
rattus_norvegicus	Epb41	ENSRNOG00000010037
drosophila_melanogaster	yrt	FBGN0004049
drosophila_melanogaster	cora	FBGN0010434
drosophila_melanogaster	Frmd5	FBGN0032225
caenorhabditis_elegans	erm-1	WBGENE00001333
caenorhabditis_elegans	frm-1	WBGENE00001488
caenorhabditis_elegans		WBGENE00001489
caenorhabditis_elegans	frm-4	WBGENE00001491

Paralogs (10): MYLIP (ENSG00000007944), EPB41L2 (ENSG00000079819), EPB41L3 (ENSG00000082397), EPB41L1 (ENSG00000088367), EPB41L4B (ENSG00000095203), EPB41L5 (ENSG00000115109), EPB41L4A (ENSG00000129595), FRMD6 (ENSG00000139926), FRMD5 (ENSG00000171877), FRMD3 (ENSG00000172159)

Protein

Protein identifiers

Protein 4.1 — P11171 (reviewed: P11171)

Alternative names: 4.1R, Band 4.1, EPB4.1, Erythrocyte membrane protein band 4.1

All UniProt accessions (24): P11171, A0A1B0GWG0, A0A2R8Y420, A0A2R8Y4N6, A0A2R8Y570, A0A2R8Y5C8, A0A2R8Y5G2, A0A2R8Y5Z6, A0A2R8Y6D0, A0A2R8Y6G5, A0A2R8Y6T6, A0A2R8Y783, A0A2R8Y7N0, A0A2R8Y7Y3, A0A2R8YCW8, A0A2R8YD30, A0A2R8YFR9, A0A2R8YFU8, A0A2U3TZH6, A0A3B3ITC5, A0A3B3ITP0, A0A3B3IU06, A0A3B3IUD6, A0A994J847

UniProt curated annotations — full annotation on UniProt →

Function. Protein 4.1 is a major structural element of the erythrocyte membrane skeleton. It plays a key role in regulating membrane physical properties of mechanical stability and deformability by stabilizing spectrin-actin interaction. Recruits DLG1 to membranes. Required for dynein-dynactin complex and NUMA1 recruitment at the mitotic cell cortex during anaphase.

Subunit / interactions. Binds with a high affinity to glycophorin and with lower affinity to band III protein. Associates with the nuclear mitotic apparatus. Interacts with calmodulin. Interacts with CPAP. Interacts with DLG1. Also found to associate with contractile apparatus and tight junctions. Interacts with NUMA1; this interaction is negatively regulated by CDK1 during metaphase and promotes anaphase-specific localization of NUMA1 in symmetrically dividing cells. Interacts with ATP2B1; regulates small intestinal calcium absorption through regulation of membrane expression of ATP2B1.

Subcellular location. Cytoplasm. Cytoskeleton. Cell cortex. Nucleus.

Post-translational modifications. Phosphorylated at multiple sites by different protein kinases and each phosphorylation event selectively modulates the protein’s functions. Phosphorylation on Tyr-660 reduces the ability of 4.1 to promote the assembly of the spectrin/actin/4.1 ternary complex. O-glycosylated; contains N-acetylglucosamine side chains in the C-terminal domain.

Disease relevance. Elliptocytosis 1 (EL1) [MIM:611804] A Rhesus-linked form of hereditary elliptocytosis, a genetically heterogeneous, autosomal dominant hematologic disorder. It is characterized by variable hemolytic anemia and elliptical or oval red cell shape. The disease is caused by variants affecting the gene represented in this entry.

Isoforms (7)

UniProt ID	Names	Canonical?
P11171-1	1	yes
P11171-2	2
P11171-3	3
P11171-4	4, Erythroid
P11171-5	5, Non-erythroid A
P11171-6	6, Non-erythroid B
P11171-7	7

RefSeq proteins (22): NP_001159477, NP_001159478, NP_001159479, NP_001362942, NP_001362943, NP_001362944, NP_001362945, NP_001362946, NP_001362947, NP_001362948, NP_001362949, NP_001362950, NP_001362951, NP_001362952, NP_001362953, NP_001362954, NP_001362955, NP_001362956, NP_001362957, NP_004428, NP_976217, NP_976218 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000299	FERM_domain	Domain
IPR000798	Ez/rad/moesin-like	Family
IPR007477	SAB_dom	Domain
IPR008379	Band_4.1_C	Domain
IPR011993	PH-like_dom_sf	Homologous_superfamily
IPR014352	FERM/acyl-CoA-bd_prot_sf	Homologous_superfamily
IPR014847	FA	Domain
IPR018979	FERM_N	Domain
IPR018980	FERM_PH-like_C	Domain
IPR019747	FERM_CS	Conserved_site
IPR019748	FERM_central	Domain
IPR019749	Band_41_domain	Domain
IPR021187	EPB4.1_FERM_F1	Domain
IPR029071	Ubiquitin-like_domsf	Homologous_superfamily
IPR035963	FERM_2	Homologous_superfamily

Pfam: PF00373, PF04382, PF05902, PF08736, PF09379, PF09380

UniProt features (94 total): modified residue 26, strand 14, helix 12, sequence conflict 10, compositionally biased region 9, region of interest 8, splice variant 8, mutagenesis site 2, turn 2, chain 1, domain 1, sequence variant 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
3QIJ	X-RAY DIFFRACTION	1.8
1GG3	X-RAY DIFFRACTION	2.8
2RQ1	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P11171-F1	63.72	0.31

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Post-translational modifications (26): 14, 60, 84, 85, 95, 104, 121, 149, 151, 152, 188, 191, 222, 378, 521, 540, 542, 555, 660, 664 …

Mutagenesis-validated functional residues (2):

Position	Phenotype
60	loss of cdk1-mediated phosphorylation. abolishes targeting onto the mitotic spindle; when associated with a-712.
712	loss of cdk1-mediated phosphorylation. abolishes targeting onto the mitotic spindle; when associated with a-60.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-6794361	Neurexins and neuroligins

MSigDB gene sets: 361 (showing top): GSE18804_SPLEEN_MACROPHAGE_VS_BRAIN_TUMORAL_MACROPHAGE_UP, ATF_B, GOBP_DIGESTION, BROWNE_HCMV_INFECTION_6HR_DN, GOBP_RESPONSE_TO_FLUID_SHEAR_STRESS, PEREZ_TP63_TARGETS, GOBP_POSITIVE_REGULATION_OF_PROTEIN_LOCALIZATION, AREB6_01, KEGG_TIGHT_JUNCTION, RIZKI_TUMOR_INVASIVENESS_3D_DN, GOBP_PROTEIN_LOCALIZATION_TO_CELL_PERIPHERY, GOBP_MONOATOMIC_CATION_TRANSPORT, AGGCACT_MIR5153P, PUJANA_CHEK2_PCC_NETWORK, GOBP_POSITIVE_REGULATION_OF_PROTEIN_LOCALIZATION_TO_CELL_PERIPHERY

GO Biological Process (7): actin cytoskeleton organization (GO:0030036), cortical actin cytoskeleton organization (GO:0030866), actomyosin structure organization (GO:0031032), cell division (GO:0051301), regulation of calcium ion transport (GO:0051924), regulation of intestinal absorption (GO:1904478), positive regulation of protein localization to cell cortex (GO:1904778)

GO Molecular Function (9): actin binding (GO:0003779), structural constituent of cytoskeleton (GO:0005200), calmodulin binding (GO:0005516), 1-phosphatidylinositol binding (GO:0005545), spectrin binding (GO:0030507), phosphoprotein binding (GO:0051219), structural molecule activity (GO:0005198), protein binding (GO:0005515), cytoskeletal protein binding (GO:0008092)

GO Cellular Component (15): cytosol (GO:0005829), cytoskeleton (GO:0005856), plasma membrane (GO:0005886), cell cortex (GO:0005938), spectrin-associated cytoskeleton (GO:0014731), basolateral plasma membrane (GO:0016323), nuclear body (GO:0016604), cell junction (GO:0030054), cortical cytoskeleton (GO:0030863), protein-containing complex (GO:0032991), intercellular bridge (GO:0045171), mitotic spindle (GO:0072686), nucleus (GO:0005634), cytoplasm (GO:0005737), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Protein-protein interactions at synapses	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
cytoskeleton	3
protein binding	3
cytoskeleton organization	2
actin cytoskeleton organization	2
cytoskeletal protein binding	2
cytoplasm	2
intracellular membraneless organelle	2
cell periphery	2
actin filament-based process	1
cortical cytoskeleton organization	1
cellular process	1
calcium ion transport	1
regulation of metal ion transport	1
regulation of digestive system process	1
intestinal absorption	1
protein localization to cell cortex	1
positive regulation of protein localization to cell periphery	1
regulation of protein localization to cell cortex	1
structural molecule activity	1
phospholipid binding	1
protein-containing complex binding	1
molecular_function	1
binding	1
membrane	1
basal plasma membrane	1
plasma membrane region	1
nucleoplasm	1
cell cortex	1
cellular_component	1
spindle	1
intracellular membrane-bounded organelle	1
intracellular anatomical structure	1

Protein interactions and networks

STRING

1576 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
EPB41	ANK1	P16157	997
EPB41	GYPC	P04921	996
EPB41	ANK3	Q12955	996
EPB41	ANK2	Q01484	996
EPB41	ADD1	P35611	994
EPB41	ADD2	P35612	993
EPB41	ADD3	Q9UEY8	993
EPB41	DMTN	Q08495	989
EPB41	SPTB	P11277	972
EPB41	EZR	P15311	935
EPB41	CADM1	Q9BY67	917
EPB41	RDX	P35241	894
EPB41	DLG1	Q12959	892
EPB41	SLC4A1	P02730	890
EPB41	MPP1	Q00013	871

IntAct

182 interactions, top by confidence:

A	B	Type	Score
MED4	MED19	psi-mi:“MI:2364”(proximity)	0.900
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
YWHAG	BLTP3B	psi-mi:“MI:0914”(association)	0.640
DDAH2	EPB41L2	psi-mi:“MI:0914”(association)	0.640
SNRPB	SART1	psi-mi:“MI:0914”(association)	0.640
YWHAH	BLTP3B	psi-mi:“MI:0914”(association)	0.570
EPB41L1	AP3B1	psi-mi:“MI:0914”(association)	0.530
EPB41L3	AP3B1	psi-mi:“MI:0914”(association)	0.530
YWHAQ	PLEKHG3	psi-mi:“MI:0914”(association)	0.480
	MYL12B	psi-mi:“MI:0914”(association)	0.460
CASK	EPB41	psi-mi:“MI:0407”(direct interaction)	0.440
NSD3	EPB41	psi-mi:“MI:0915”(physical association)	0.400
EPB41	GYPC	psi-mi:“MI:0915”(physical association)	0.400
ORF73	ECI2	psi-mi:“MI:0914”(association)	0.350
BCAR1	PSMD11	psi-mi:“MI:0914”(association)	0.350
BCAR1	MYO1C	psi-mi:“MI:0914”(association)	0.350
ESR1	ESYT2	psi-mi:“MI:0914”(association)	0.350
LRRK2		psi-mi:“MI:0914”(association)	0.350
YWHAG	C1orf226	psi-mi:“MI:0914”(association)	0.350
KDM4C	SMCHD1	psi-mi:“MI:0914”(association)	0.350
EEF2K	CNOT1	psi-mi:“MI:0914”(association)	0.350
CHEK2	EPB41	psi-mi:“MI:0914”(association)	0.350
NFE2L2	MYO1D	psi-mi:“MI:0914”(association)	0.350
FGFR3	U2SURP	psi-mi:“MI:0914”(association)	0.350
MAPT	SHTN1	psi-mi:“MI:0914”(association)	0.350

BioGRID (170): EPB41 (Two-hybrid), RWDD2B (Two-hybrid), ZCCHC10 (Two-hybrid), EPB41 (Affinity Capture-MS), EPB41 (Co-fractionation), SF3A3 (Co-fractionation), EPB41 (Affinity Capture-MS), EPB41 (Proximity Label-MS), EPB41 (Proximity Label-MS), EPB41 (Proximity Label-MS), EPB41 (Affinity Capture-RNA), EPB41 (Affinity Capture-MS), EPB41 (Affinity Capture-RNA), MYH9 (Affinity Capture-MS), EPB41 (Affinity Capture-MS)

ESM2 similar proteins: A2AD83, A4Q9F0, A6QP06, A7KAX9, B2RYE5, B4K6T8, F7E540, G5EEW9, O00443, O13839, O43283, O96838, P11171, P11434, P48193, Q12923, Q14693, Q22744, Q3V0G7, Q5FVG2, Q5R8N8, Q5R8X7, Q5RAY1, Q61194, Q64512, Q6DTM3, Q6GPD0, Q6Q7P4, Q6ZT98, Q6ZUT3, Q811P8, Q8BGS1, Q8BPQ7, Q8CHB8, Q8K3Y6, Q8WYB5, Q91573, Q91ZP3, Q96HH9, Q99PI5

Diamond homologs: A2A2Y4, A2AD83, A2ALK8, B2RYE5, F1LYQ8, F1P065, F8VPU2, O43491, O57457, O70318, O94887, P11171, P11434, P26045, P28191, P29074, P48193, P52963, Q0P4Q4, Q54K81, Q58CU2, Q5FVG2, Q5R803, Q5RAB8, Q6P5H6, Q6Q7P4, Q6ZUT3, Q7Z6J6, Q8BGS1, Q8BHD4, Q91VS8, Q9H329, Q9H4G0, Q9HCM4, Q9HCS5, Q9JMC8, Q9MYU8, Q9N179, Q9V8R9, Q9WTP0

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
EGFR	down-regulates	EPB41	phosphorylation
EPB41	“up-regulates activity”	NUMA1	relocalization
EPB41	“form complex”	“4.1 complex”	binding
EPB41	“up-regulates activity”	DLG1	relocalization

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 194 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
Antigen processing: Ub, ATP-independent proteasomal degradation	7	24.4×	3e-07
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	5	20.5×	4e-05
Vif-mediated degradation of APOBEC3G	10	15.5×	2e-07
RHO GTPases activate PKNs	8	15.5×	8e-07
Regulation of activated PAK-2p34 by proteasome mediated degradation	9	15.3×	3e-07
AUF1 (hnRNP D0) binds and destabilizes mRNA	10	15.1×	2e-07
GSK3B and BTRC:CUL1-mediated-degradation of NFE2L2	10	15.1×	2e-07
Regulation of ornithine decarboxylase (ODC)	9	14.9×	3e-07

Disease & clinical

Clinical variants and AI predictions

ClinVar

303 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	17
Likely pathogenic	17
Uncertain significance	164
Likely benign	40
Benign	18

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
16711	NM_203342.2(EPB41):c.-159_159del	Pathogenic
16712	NM_004437.3(EPB41):c.1219_1587del	Pathogenic
16713	NM_004437.3(EPB41):c.1219_1458del	Pathogenic
16714	NM_001376013.1(EPB41):c.629T>G (p.Met210Arg)	Pathogenic
16715	NM_001376013.1(EPB41):c.629T>C (p.Met210Thr)	Pathogenic
221297	NM_001376013.1(EPB41):c.1071_1077del (p.Asn358fs)	Pathogenic
2779958	NM_001376013.1(EPB41):c.2143C>T (p.Arg715Ter)	Pathogenic
2819907	NM_001376013.1(EPB41):c.1473dup (p.Thr492fs)	Pathogenic
3341889	NM_001376013.1(EPB41):c.1059dup (p.Lys354Ter)	Pathogenic
3667832	NM_001376013.1(EPB41):c.820C>T (p.Gln274Ter)	Pathogenic
3727875	NM_001376013.1(EPB41):c.1301G>A (p.Trp434Ter)	Pathogenic
3766780	NM_001376013.1(EPB41):c.741del (p.Glu248fs)	Pathogenic
4279438	GRCh37/hg19 1p35.3(chr1:29242759-29427780)x1	Pathogenic
4728387	NM_001376013.1(EPB41):c.659_660del (p.Thr220fs)	Pathogenic
4736259	NM_001376013.1(EPB41):c.2179G>T (p.Glu727Ter)	Pathogenic
4779011	NM_001376013.1(EPB41):c.742G>T (p.Glu248Ter)	Pathogenic
620455	NM_001376013.1(EPB41):c.666T>G (p.Tyr222Ter)	Pathogenic
1163136	NM_001376013.1(EPB41):c.1744dup (p.Thr582fs)	Likely pathogenic
1324333	NM_001376013.1(EPB41):c.712C>T (p.Arg238Ter)	Likely pathogenic
1324334	NM_001376013.1(EPB41):c.1175del (p.Lys392fs)	Likely pathogenic
1330707	NM_001376013.1(EPB41):c.2065A>T (p.Lys689Ter)	Likely pathogenic
2440049	NM_001376013.1(EPB41):c.1330dup (p.Arg444fs)	Likely pathogenic
2446433	NM_001376013.1(EPB41):c.768G>A (p.Trp256Ter)	Likely pathogenic
2631490	NM_001376013.1(EPB41):c.1652C>A (p.Ser551Ter)	Likely pathogenic
2690597	NM_001376013.1(EPB41):c.2085_2089del (p.Val696fs)	Likely pathogenic
2855191	NM_001376013.1(EPB41):c.1636+1G>T	Likely pathogenic
3391109	NM_001376013.1(EPB41):c.902C>G (p.Thr301Arg)	Likely pathogenic
4081367	NM_001376013.1(EPB41):c.818del (p.Lys273fs)	Likely pathogenic
4081369	NM_001376013.1(EPB41):c.1295del (p.Phe432fs)	Likely pathogenic
4081370	NM_001376013.1(EPB41):c.1609A>T (p.Lys537Ter)	Likely pathogenic

SpliceAI

4279 predictions. Top by Δscore:

Variant	Effect	Δscore
1:28887208:CAGG:C	donor_loss	1.0000
1:28887211:G:GA	donor_loss	1.0000
1:28987426:A:AG	acceptor_gain	1.0000
1:28987427:A:G	acceptor_gain	1.0000
1:28987428:T:G	acceptor_gain	1.0000
1:28987429:A:AG	acceptor_gain	1.0000
1:28987430:G:GG	acceptor_gain	1.0000
1:28987430:GC:G	acceptor_gain	1.0000
1:28987430:GCA:G	acceptor_gain	1.0000
1:28987430:GCAA:G	acceptor_gain	1.0000
1:28987430:GCAAC:G	acceptor_gain	1.0000
1:28987906:G:GC	donor_loss	1.0000
1:28987907:T:A	donor_loss	1.0000
1:28993303:T:A	acceptor_gain	1.0000
1:29015686:TTATA:T	acceptor_loss	1.0000
1:29015687:TATAG:T	acceptor_loss	1.0000
1:29015689:TAG:T	acceptor_loss	1.0000
1:29015691:GGT:G	acceptor_gain	1.0000
1:29015763:ACAAG:A	donor_loss	1.0000
1:29015764:CAAGG:C	donor_loss	1.0000
1:29015768:G:GA	donor_loss	1.0000
1:29015769:T:A	donor_loss	1.0000
1:29018439:ACAG:A	donor_loss	1.0000
1:29018442:GG:G	donor_loss	1.0000
1:29018443:G:A	donor_loss	1.0000
1:29030388:A:AG	acceptor_gain	1.0000
1:29030389:T:G	acceptor_gain	1.0000
1:29030393:A:AG	acceptor_gain	1.0000
1:29030394:T:G	acceptor_gain	1.0000
1:29030396:A:AG	acceptor_gain	1.0000

AlphaMissense

5681 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
1:29018244:T:C	L309P	1.000
1:29030419:G:C	A382P	1.000
1:29033118:T:C	L413P	1.000
1:29033120:G:C	G414R	1.000
1:29033139:T:C	L420P	1.000
1:29033145:T:A	V422D	1.000
1:29033174:T:C	F432L	1.000
1:29033175:T:C	F432S	1.000
1:29033176:C:A	F432L	1.000
1:29033176:C:G	F432L	1.000
1:29033180:T:A	W434R	1.000
1:29033180:T:C	W434R	1.000
1:29033182:G:C	W434C	1.000
1:29033182:G:T	W434C	1.000
1:29033193:T:C	L438P	1.000
1:29033195:A:G	K439E	1.000
1:29033208:A:T	K443I	1.000
1:29033220:T:C	F447S	1.000
1:29033226:T:A	I449N	1.000
1:29033228:A:G	K450E	1.000
1:29035853:T:C	F465L	1.000
1:29035854:T:C	F465S	1.000
1:29035855:C:A	F465L	1.000
1:29035855:C:G	F465L	1.000
1:29035860:T:C	L467P	1.000
1:29035878:C:A	A473D	1.000
1:29035889:T:A	W477R	1.000
1:29035889:T:C	W477R	1.000
1:29035891:G:C	W477C	1.000
1:29035891:G:T	W477C	1.000

dbSNP variants (sampled 300 via entrez): RS1000014912 (1:29119298 ATG>A), RS1000015671 (1:28924821 G>C), RS1000022462 (1:29037490 C>T), RS1000037036 (1:29057765 A>G,T), RS1000055003 (1:29106735 G>A,T), RS1000060399 (1:29106449 T>C), RS1000065497 (1:29011228 G>T), RS1000068067 (1:28925169 T>C), RS1000071955 (1:29025713 T>C), RS1000085601 (1:29057486 T>G), RS1000086789 (1:28965428 A>G,T), RS1000090746 (1:29106460 T>C), RS1000120286 (1:29113276 G>A), RS1000121131 (1:29042492 T>G), RS1000130058 (1:28971180 CTTTTTTTTTTTTTTTTTT>C,CTTTT,CTTTTT,CTTTTTT,CTTTTTTT,CTTTTTTTT,CTTTTTTTTT,CTTTTTTTTTT,CTTTTTTTTTTT,CTTTTTTTTTTTT,CTTTTTTTTTTTTTT,CTTTTTTTTTTTTTTT,CTTTTTTTTTTTTTTTT,CTTTTTTTTTTTTTTTTT,CTTTTTTTTTTTTTTTTTTT,CTTTTTTTTTTTTTTTTTTTT,CTTTTTTTTTTTTTTTTTTTTT,CTTTTTTTTTTTTTTTTTTTTTT,CTTTTTTTTTTTTTTTTTTTTTTT,CTTTTTTTTTTTTTTTTTTTTTTTT,CTTTTTTTTTTTTTTTTTTTTTTTTT,CTTTTTTTTTTTTTTTTTTTTTTTTTT,CTTTTTTTTTTTTTTTTTTTTTTTTTTT,CTTTTTTTTTTTTTTTTTTTTTTTTTTTT,CTTTTTTTTTTTTTTTTTTTTTTTTTTTTT,CTTTTTTTTTTTTTTTTTTTTTTTTTTTTTT,CTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTT,CTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTT,CTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTT,CTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTT,CTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTT,CTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTT,CTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTT,CTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTT,CTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTT,CTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTT,CTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTT,CTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTT,CTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTT,CTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTT,CTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTTT)

Disease associations

OMIM: gene MIM:130500 | disease phenotypes: MIM:611804

GenCC curated gene-disease

Disease	Classification	Inheritance
elliptocytosis 1	Definitive	Semidominant
hereditary elliptocytosis	Supportive	Autosomal dominant

Mondo (2): elliptocytosis 1 (MONDO:0012731), hereditary elliptocytosis (MONDO:0017319)

Orphanet (1): Hereditary elliptocytosis (Orphanet:288)

HPO phenotypes

26 total (26 of 26 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0000007	Autosomal recessive inheritance
HP:0000952	Jaundice
HP:0000980	Pallor
HP:0001081	Cholelithiasis
HP:0001744	Splenomegaly
HP:0001789	Hydrops fetalis
HP:0001877	Abnormal erythrocyte morphology
HP:0001878	Hemolytic anemia
HP:0001923	Reticulocytosis
HP:0001945	Fever
HP:0002007	Frontal bossing
HP:0002027	Abdominal pain
HP:0002904	Hyperbilirubinemia
HP:0003265	Neonatal hyperbilirubinemia
HP:0003546	Exercise intolerance
HP:0004445	Elliptocytosis
HP:0004446	Stomatocytosis
HP:0004447	Poikilocytosis
HP:0004804	Congenital hemolytic anemia
HP:0005502	Increased red cell osmotic fragility
HP:0006579	Prolonged neonatal jaundice
HP:0008897	Postnatal growth retardation
HP:0012378	Fatigue
HP:0025143	Chills
HP:0200042	Skin ulcer

GWAS associations

15 associations (top):

Study	Trait	p-value
GCST002337_76	Amyotrophic lateral sclerosis (sporadic)	6.000000e-06
GCST007277_1	Tourette syndrome	2.000000e-06
GCST010083_183	Hemoglobin levels	1.000000e-09
GCST012325_1	HDL levels x SSRI defined daily dose interaction in schizophrenia or bipolar disorder	4.000000e-07
GCST90002385_607	High light scatter reticulocyte count	2.000000e-11
GCST90002386_312	High light scatter reticulocyte percentage of red cells	7.000000e-11
GCST90002391_58	Mean corpuscular hemoglobin concentration	1.000000e-11
GCST90002396_122	Mean reticulocyte volume	5.000000e-12
GCST90002396_123	Mean reticulocyte volume	1.000000e-13
GCST90002396_124	Mean reticulocyte volume	7.000000e-74
GCST90002397_622	Mean spheric corpuscular volume	4.000000e-10
GCST90002397_623	Mean spheric corpuscular volume	4.000000e-77
GCST90002401_11	Platelet distribution width	6.000000e-16
GCST90002405_600	Reticulocyte count	9.000000e-24
GCST90002406_137	Reticulocyte fraction of red cells	6.000000e-25

EFO canonical traits (7, from GWAS)

EFO ID	Trait name
EFO:0004509	hemoglobin measurement
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0005658	response to selective serotonin reuptake inhibitor
EFO:0007986	reticulocyte count
EFO:0004528	mean corpuscular hemoglobin concentration
EFO:0010701	mean reticulocyte volume
EFO:0007984	platelet component distribution width

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D004612	Elliptocytosis, Hereditary	C15.378.050.141.150.365; C16.320.070.365
C567520	Elliptocytosis 1 (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL6066965 (SINGLE PROTEIN)

PharmGKB: 1 entry (VIP=true, CPIC=false)

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs6702335	Efficacy	3	bupropion;nicotine	Tobacco Use Disorder

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs6702335	EPB41	3	3.25	1	bupropion;nicotine

ChEMBL bioactivities

2 potent at pChembl≥5 of 2 total, top 2 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
8.11	Kd	7.837	nM	CHEMBL5653589
8.11	ED50	7.837	nM	CHEMBL5653589

PubChem BioAssay actives

1 with measured affinity, of 2 total; 1 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148322: Binding affinity to human EPB41 incubated for 45 mins by Kinobead based pull down assay	kd	0.0078	uM

CTD chemical–gene interactions

39 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, decreases expression, increases methylation	5
sodium arsenite	affects methylation, decreases expression, increases abundance, increases expression	4
bisphenol A	decreases expression, increases expression, increases methylation	3
Acetaminophen	decreases expression	3
Air Pollutants	decreases expression, increases abundance, increases expression	2
Arsenic	affects methylation, increases abundance, increases expression	2
Benzo(a)pyrene	affects methylation, decreases expression	2
Cyclosporine	increases expression	2
aristolochic acid I	decreases expression	1
GSK-J4	increases expression	1
FR900359	affects phosphorylation	1
9-hydroxyoctadecadienoic acid	increases expression	1
pirinixic acid	increases expression, affects binding, increases activity	1
trichostatin A	increases expression	1
11-nor-delta(9)-tetrahydrocannabinol-9-carboxylic acid	affects methylation, increases abundance	1
tris(1,3-dichloro-2-propyl)phosphate	increases expression	1
butyraldehyde	decreases expression	1
manganese chloride	increases abundance, increases expression	1
potassium chromate(VI)	increases expression	1
coumarin	decreases phosphorylation	1
di-n-butylphosphoric acid	affects expression	1
chromium hexavalent ion	decreases expression	1
CGP 52608	affects binding, increases reaction	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
bisphenol S	decreases methylation	1
LDN 193189	affects cotreatment, increases expression	1
Decitabine	affects expression	1
Sunitinib	increases expression	1
Vorinostat	decreases expression	1
Caffeine	decreases phosphorylation	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL5651364	Binding	Binding affinity to human EPB41 incubated for 45 mins by Kinobead based pull down assay	NVP-BHG712: Effects of Regioisomers on the Affinity and Selectivity toward the EPHrin Family. — ChemMedChem

Clinical trials (associated diseases)

2 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT00723567	Not specified	COMPLETED	A Novel Mutation of the Spectrin Gene
NCT01923376	Not specified	WITHDRAWN	Hepatic Encephalopathy: Lactulose or Polyethylene Glycol (H.E.L.P.)