KATNIP

protein-coding

katanin interacting protein

Gene summary

This gene encodes a novel, evolutionarily conserved, ciliary protein. In human hTERT-RPE1 cells, the protein is found at the base of cilia, decorating the ciliary axoneme, and enriched at the ciliary tip. The protein binds to microtubules in vitro and regulates their stability when it is overexpressed. A null mutation in this gene has been associated with Joubert syndrome, a recessive disorder that is characterized by a distinctive mid-hindbrain and cerebellar malformation and is also often associated with wider ciliopathy symptoms. Consistently, in a serum-starvation ciliogenesis assay, human fibroblast cells derived from patients with the mutation display a reduced number of ciliated cells with abnormally long cilia. [provided by RefSeq, Feb 2016]

Previous symbols:

KIAA0556

MANE transcript

NM_015202.5

Inheritance

ClinVar variants

P:59U:418B:295

Top phenotype

Joubert syndrome 26

gnomAD constraint

pLI —, LoF o/e 0.73

Max pathogenic AF

—

Genomic locus

chr16:27,550,133-27,780,344

External References & Databases

Ensembl (ENSG00000047578)

Transcript & Mutation Effects

hg38 • Region Span ~230.2 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

ciliopathyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0005308

Submitter: ClinGen

*KATNIP* was first reported in relation to autosomal recessive ciliopathy-KATNIP (MONDO:0005308) in 2015 (Sanders AA et al., PMID: 26714646). Individuals with ciliopathy *KATNIP* presented with Joubert syndrome and abnormalities of the anterior and posterior pituitary gland and sometimes retinal dystrophy, cleft lip/palate, agenesis of the corpus callosum, and hypothalamic hamartoma. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no differences in molecular mechanism and inheritance pattern and no significant phenotypic variability. *KATNIP* has previously been associated with only one disease entity: autosomal recessive Joubert syndrome 26 (MIM #616784). Eight variants (nonsense, frameshift, splice-site) that have been reported in 6 probands in 6 publications (PMIDs: 26714646, 27245168, 31197031, 36580738, 32164589, 30982090) are included in this curation. The mechanism of pathogenicity is reported to be loss of function. This gene-disease relationship is also supported by experimental evidence, most importantly protein interaction studies showing *KATNIP* interacting with ciliary components and microtubule-regulating katanins, patient-derived fibroblasts showing primary cilium alterations, and a knockdown zebrafish model presenting a ciliopathy phenotype (PMIDs: 27245168 & 26714646). In summary, there is “Definitive” evidence supporting the relationship between *KATNIP* and autosomal recessive ciliopathy- *KATNIP* (MONDO:0005308). This has been repeatedly demonstrated in both the research and clinical diagnostic settings and upheld over time. This classification was approved by the ClinGen Kidney Cystic and Ciliopathy Disorders GCEP on 07/10/2023.

Joubert syndrome 26STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014771

Submitter: Labcorp Genetics (formerly Invitae)

Joubert syndrome 26STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014771

Submitter: PanelApp Australia

Joubert syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0018772

Submitter: Orphanet

Clinical Genomic Database (CGD)

Joubert syndrome 26AR

Manifestation: Endocrine; Neurologic

Intervention: Endocrine

Rationale: Individuals have been described with panhypopituitarism, and awareness may allow early diagnosis and medical management (eg, with hormone replacement therapy)

Refs: 26714646

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to KATNIP variants in ClinVar

11 Conditions Cataloged

not providedTotal: 557

not specifiedTotal: 494

KATNIP-related disorderTotal: 57

Joubert syndrome 26Total: 33

KIAA0556-related disordersTotal: 9

KATNIP & KIAA0556-related disordersTotal: 8

KATNIP-related disordersTotal: 5

CiliopathyTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_015202.5. 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			6 clinvar	213 clinvar	9 clinvar	228
missense		2 clinvar	401 clinvar	64 clinvar	8 clinvar	475
nonsense	4 clinvar	10 clinvar	1 clinvar			15
start loss						0
frameshift	9 clinvar	17 clinvar	2 clinvar			28
splice donor/acceptor (+/-2bp)		17 clinvar	8 clinvar	1 clinvar		26
Total	13	46	418	278	17	772

Highest pathogenic variant AF is 0.00028563922

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 32 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_015202.5	RefSeq	NP_056017.4	28	MANE Select
ENST00000261588.10	Ensembl	ENSP00000261588.4	28	MANE Select
ENST00000565672.5	Ensembl	ENSP00000455380.1	2	Standard
ENST00000568258.5	Ensembl	ENSP00000454884.1	7	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Cellular Component

extracellular space
cytoplasm
cytoskeleton
cell projection

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000261588
Coding exons: 28
Length: 230237
Individuals with no LoFs: 125415
Homozygous LoFs: 1
Heterozygous LoFs: 332
Defined: 125748
p: 0.00133

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	-0.111	987	977	1.01	0.0000604	10569
Missense (PolyPhen)		329	356.56	0.92271		3987
Synonymous	-0.176	417	412	1.01	0.0000286	3194
Loss of Function	2.23	57	78.3	0.728	0.00000422	863

Population LoF Frequency

Population	CAF	p-value	Status
African	0.0011	0.0010	notable
Latino/Admixed American	0.0010	0.0010	notable
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0.00060	0.00060	rare
Finnish	0.00065	0.00065	rare
European (Non-Finnish)	0.0015	0.0015	notable
South Asian	0.0022	0.0022	notable
Other	0.0028	0.0028	notable

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: May influence the stability of microtubules (MT), possibly through interaction with the MT-severing katanin complex. {ECO:0000269|PubMed:26714646}.;
Disease: DISEASE: Joubert syndrome 26 (JBTS26) [MIM:616784]: A form of Joubert syndrome, a disorder presenting with cerebellar ataxia, oculomotor apraxia, hypotonia, neonatal breathing abnormalities and psychomotor delay. Neuroradiologically, it is characterized by cerebellar vermian hypoplasia/aplasia, thickened and reoriented superior cerebellar peduncles, and an abnormally large interpeduncular fossa, giving the appearance of a molar tooth on transaxial slices (molar tooth sign). Additional variable features include retinal dystrophy, renal disease, liver fibrosis, and polydactyly. JBTS26 inheritance is autosomal recessive. {ECO:0000269|PubMed:26714646}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.0930

Intolerance Scores

LoFtool: 0.918
RVIS EVS: 0.83
RVIS percentile EVS: 88.13

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.361

Gene Damage Prediction

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