ELP1

protein-coding

elongator acetyltransferase complex subunit 1, the group of Elongator acetyltransferase complex

Gene summary

The protein encoded by this gene is a scaffold protein and a regulator for three different kinases involved in proinflammatory signaling. The encoded protein can bind NF-kappa-B-inducing kinase and I-kappa-B kinases through separate domains and assemble them into an active kinase complex. Mutations in this gene have been associated with familial dysautonomia. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jan 2016]

Previous symbols:

DYS
IKBKAP

MANE transcript

NM_003640.5

Inheritance

AD, AR

ClinVar variants

P:477U:858B:628

Top phenotype

Neuropathy, hereditary sensory and autonomic, type III

gnomAD constraint

pLI —, LoF o/e 0.58

Max pathogenic AF

—

Genomic locus

chr9:108,866,898-108,934,328

External References & Databases

Ensembl (ENSG00000070061)

Transcript & Mutation Effects

hg38 • Region Span ~67.4 kb

Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

medulloblastomaDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0007959

Submitter: Natera

Riley-Day syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009131

Submitter: Natera

Riley-Day syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009131

Submitter: Orphanet

medulloblastomaSTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0007959

Submitter: PanelApp Australia

primary dysautonomiaDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0021809

Submitter: Myriad Women's Health

Riley-Day syndromeDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0009131

Submitter: G2P

neurodevelopmental disorderLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0700092

Submitter: PanelApp Australia

Riley-Day syndromeMODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0009131

Submitter: ClinGen

ELP1 was first reported in relation to Autosomal Recessive Familial Dysautonomia (FD) in 2001 (Anderson et al, PMID: 11179021; Slaugenhaupt, PMID: 11179008). At least 2 missense variants and 1 splice region variant have been reported in humans. The splice region variant, c.2204+6T>C, is a founder variant in the Ashkenazi Jewish (AJ) population, found in >99.5% of patients with the disease. A common ancestral haplotype (FD major haplotype) is shared among all these individuals. Evidence supporting this gene-disease relationship includes case-level and experimental data. Variants in this gene have been reported in more than 32 probands in 3 publications (PMID: 11179021, 11179008, 12687659). All individuals except one were of AJ extraction. The one other individual had one parent who was AJ and had the splice region variant. The mechanism for disease is expected to be haploinsufficiency. Individuals with FD have the defective ELP1 protein, but also express the wild-type. There is tissue-specific expression of variant ELP1 in neuronal tissues, where the amount of wild-type ELP1 is lesser than the threshold for normal cell function and development. This gene-disease association is supported by functional evidence from expression in non-patient cells, animal models, rescue evidence in animal models and humans. The development of a mouse model for FD was a result of several attempts. Knock-out of Elp1 in mice was embryonic lethal. Introducing the splice region variant in the mouse genome did not cause a disruption in Elp1, perhaps due to better splicing efficiency in mice. Introducing the human FD transgene reproduced the splicing defect in mice; however, no FD phenotype was observed due to the expression of endogenous mouse Elp1. The FD phenotype was recapitulated when the human FD transgene was introduced in Elp1-Δ20/flox mice (PMID: 26769677, 22922231). The plant cytokinin, Kinetin, is shown to mitigate the splicing defect and increase the expression of wild-type ELP1 mRNA in humans and mouse models. Human wild-type ELP1 was also shown to rescue embryonic lethality in Elp1-knockout mice. Additionally, a transcriptomic analysis (PMID: 38698036) of neuronal tissues in a relevant ELP1 mouse model found significantly more differentially expressed genes in the peripheral nervous system involved in peptidergic nociceptors and myelinated sensory neurons. Both relevant in the disease mechanism of familial dysautonomia. In summary, this gene-disease relationship is classified moderate; however, since most of the affected individuals have the same founder variant, scoring them additively will result in this gene-disease relationship being definitive. While more evidence regarding this gene-disease relationship will strengthen the classification, no convincing contradictory evidence has emerged.

primary dysautonomiaSTRONG

Inheritance Pattern: AR

Disease ID:MONDO:0021809

Submitter: PanelApp Australia

medulloblastomaLIMITED

Inheritance Pattern: AD

Disease ID:MONDO:0007959

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Neuropathy, hereditary sensory and autonomic, type IIIAR

Manifestation: 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: One report has described possible increased tumorigenesis in affected individuals; Individuals may be prone to injury due to pain insensitivity

Refs: 18118947; 14071043; 14245781; 4322121; 7374014; 7254974; 7097419; 3585611; 11179021; 11179008; 12406829; 12546638; 15088259; 19651702; 19914433; 20301359; 22129610; 22170819; 22229594; 22571291; 22727867; 22739220; 22850346

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to ELP1 variants in ClinVar

12 Conditions Cataloged

not providedTotal: 1811

Familial dysautonomiaTotal: 1149

not specifiedTotal: 474

MedulloblastomaTotal: 369

ELP1-related disorderTotal: 104

ELP1-Associated MedulloblastomaTotal: 29

Hereditary sensory and autonomic neuropathyTotal: 3

Charcot-Marie-Tooth diseaseTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_003640.5. 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.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous	1 clinvar		39 clinvar	588 clinvar	5 clinvar	633
missense		2 clinvar	800 clinvar	32 clinvar	1 clinvar	835
nonsense	28 clinvar	108 clinvar	4 clinvar			140
start loss		1 clinvar				1
frameshift	79 clinvar	138 clinvar	1 clinvar			218
splice donor/acceptor (+/-2bp)		120 clinvar	14 clinvar	2 clinvar		136
Total	108	369	858	622	6	1963

Highest pathogenic variant AF is 0.00039409514

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 47 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_003640.5	RefSeq	NP_003631.2	36	MANE Select
ENST00000374647.10	Ensembl	ENSP00000363779.5	36	MANE Select
NM_001318360.2	RefSeq	NP_001305289.1	34	Standard
NM_001330749.2	RefSeq	NP_001317678.1	27	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
elp1	Danio rerio	Structure: intestine Quality: decreased amount abnormal

Gene / Model

Organism

Observed Phenotype

elp1

Danio rerio

Structure: intestine

Quality: decreased amount

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

EGF-Ncore
Chromatin modifying enzymes
HATs acetylate histones
IL1
Chromatin organization

Biological Process

tRNA wobble uridine modification
regulation of transcription by RNA polymerase II
transcription elongation from RNA polymerase II promoter
protein phosphorylation
immune response

Molecular Function

RNA polymerase II complex binding
protein binding
phosphorylase kinase regulator activity

Cellular Component

nucleolus
cytoplasm
cytosol
transcription elongation factor complex
Elongator holoenzyme complex

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000374647
Coding exons: 36
Length: 66600
Individuals with no LoFs: 125624
Homozygous LoFs: 0
Heterozygous LoFs: 124
Defined: 125748
p: 0.000493

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.0798	698	692	1.01	0.0000369	8763
Missense (PolyPhen)		253	256.28	0.9872		3324
Synonymous	0.0676	255	256	0.995	0.0000140	2498
Loss of Function	3.54	47	81.5	0.577	0.00000423	957

Population LoF Frequency

Population	CAF	p-value	Status
African	0.00092	0.00092	rare
Latino/Admixed American	0.00061	0.00058	rare
Ashkenazi Jewish	0.00020	0.00020	rare
East Asian	0.00071	0.00071	rare
Finnish	0.000093	0.000092	rare
European (Non-Finnish)	0.00047	0.00047	rare
South Asian	0.00052	0.00052	rare
Other	0.00049	0.00049	rare

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May act as a scaffold protein that may assemble active IKK-MAP3K14 complexes (IKKA, IKKB and MAP3K14/NIK).;
Disease: DISEASE: Neuropathy, hereditary sensory and autonomic, 3 (HSAN3) [MIM:223900]: A form of hereditary sensory and autonomic neuropathy, a genetically and clinically heterogeneous group of disorders characterized by degeneration of dorsal root and autonomic ganglion cells, and by sensory and/or autonomic abnormalities. HSAN3 patients manifest a variety of symptoms such as alacrima, decreased taste, decreased sensitivity to pain and temperature, vasomotor instability, hypoactive or absent deep tendon reflexes, vomiting crises, and gastrointestinal dysfunction. {ECO:0000269|PubMed:11179008, ECO:0000269|PubMed:11179021}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.553

Intolerance Scores

RVIS EVS: 0.84
RVIS percentile EVS: 88.18

Essentials

Essential (gene trap): E