LZTFL1

protein-coding

leucine zipper transcription factor like 1

Gene summary

This gene encodes a ubiquitously expressed protein that localizes to the cytoplasm. This protein interacts with Bardet-Biedl Syndrome (BBS) proteins and, through its interaction with BBS protein complexes, regulates protein trafficking to the ciliary membrane. Nonsense mutations in this gene cause a form of Bardet-Biedl Syndrome; a ciliopathy characterized in part by polydactyly, obesity, cognitive impairment, hypogonadism, and kidney failure. This gene may also function as a tumor suppressor; possibly by interacting with E-cadherin and the actin cytoskeleton and thereby regulating the transition of epithelial cells to mesenchymal cells. [provided by RefSeq, Aug 2020]

MANE transcript

NM_020347.4

Inheritance

ClinVar variants

P:21U:110B:48

Top phenotype

Bardet-Biedl syndrome 17

gnomAD constraint

pLI —, LoF o/e 0.29

Max pathogenic AF

—

Genomic locus

chr3:45,823,316-45,916,042

External References & Databases

Ensembl (ENSG00000163818)

Transcript & Mutation Effects

hg38 • Region Span ~92.7 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

Bardet-Biedl syndromeSUPPORTIVE

Inheritance Pattern: AR

Disease ID:MONDO:0015229

Submitter: Orphanet

Bardet-Biedl syndrome 17STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014445

Submitter: PanelApp Australia

LZTFL1-related ciliopathyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:1040046

Submitter: ClinGen

*LZTFL1* was first reported in relation to an autosomal recessive ciliopathy, Bardet-Biedl syndrome 17 (BBS17), in 2012 (Marion et al, PMID: 22510444). Bardet-Biedl syndrome is a multisystem disorder characterized by retinopathy, obesity, polydactyly, intellectual disability, hypogonadotropic hypogonadism and/or genitourinary malformations, and renal malformations and/or renal disease Biallelic loss-of-function variants in at least 26 genes have been described in affected individuals. *LZTFL1* is thought to cause <1% of BBS cases (Forsyth and Gunay-Aygun, 2023, PMID: 20301537). *LZTFL1* encodes “leucine zipper transcription factor-like 1”, a ubiquitously expressed cytoplasmic protein that interacts with the BBSome and regulates protein trafficking to the ciliary membrane. Together with the BBSome, LZTFL1 controls the ciliary trafficking of smoothened (SMO) and contributes to the sonic hedgehog (SHH) pathway regulation. Six variants (two nonsense, two frameshift, one missense, and one synonymous predicted to impact splicing) have been reported in six probands in five publications (Marion et al, 2012, PMID: 22510444; Schaeffer et al, 2014, PMID: 23692385; Gumus et al, 2021, PMID: 32686083; Nawaz et al, 2023, PMID: 37239474; Gnanasekaran et al, 2023, PMID: 37431782). The individuals reported have typical features of BBS but the polydactyly of the hands is mesoaxial rather than postaxial. The mechanism of pathogenicity appears to be loss of function. Total points for genetic evidence = 11.6 points. This gene-disease relationship is also supported by experimental evidence, including the biochemical function of the gene product, which is consistent with the clinical features observed in patients (Seo et al, 2011, PMID: 22072986; Eguether et al, 2014, PMID: 25446516), observations in cells from a patient (Marion et al, 2012, PMID: 22510444), the features observed in a knock out mouse model (Datta et al, 2015, PMID: 26216965), and results of a rescue experiment (Datta et al, 2020, PMID: 32568387). More experimental evidence is available in the literature but the maximum (6 points) has already been reached. In summary, there is definitive evidence supporting the relationship between *LZTFL1* and autosomal recessive LZTFL1-related ciliopathy. This classification was approved by the ClinGen Retina Gene Curation Expert Panel on January 4th, 2024 (SOP version 10).

Bardet-Biedl syndrome 17STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014445

Submitter: Labcorp Genetics (formerly Invitae)

Bardet-Biedl syndrome 17MODERATE

Inheritance Pattern: AR

Disease ID:MONDO:0014445

Submitter: Ambry Genetics

Bardet-Biedl syndrome 17STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0014445

Submitter: G2P

Clinical Genomic Database (CGD)

Bardet-Biedl syndrome 17AR

Manifestation: Cardiovascular; Endocrine; Gastrointestinal; Musculoskeletal; Neurologic; Ophthalmologic; Renal

Intervention: Cardiovascular; Endocrine

Rationale: The condition can involve congenital cardiac anomalies, and awareness may allow early management; Medical management of obesity with melanocortin-4 receptor (MC4R) agonist (setmelanotide) may be beneficial

Refs: 17163542; 22510444; 23692385; 36356613

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to LZTFL1 variants in ClinVar

8 Conditions Cataloged

not providedTotal: 173

LZTFL1-related disorderTotal: 86

Bardet-Biedl syndrome 17Total: 48

Inborn genetic diseasesTotal: 27

not specifiedTotal: 22

Bardet-Biedl syndrome 1Total: 2

Retinal dystrophyTotal: 1

Bardet-Biedl syndromeTotal: 1

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_020347.4. 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	3 clinvar	44 clinvar		48
missense	1 clinvar		102 clinvar	4 clinvar		107
nonsense	4 clinvar	3 clinvar	1 clinvar			8
start loss			2 clinvar			2
frameshift	5 clinvar	2 clinvar				7
splice donor/acceptor (+/-2bp)		5 clinvar	2 clinvar			7
Total	10	11	110	48	0	179

Highest pathogenic variant AF is 0.000006570216

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 35 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_020347.4	RefSeq	NP_065080.1	10	MANE Select
ENST00000296135.11	Ensembl	ENSP00000296135.6	10	MANE Select
NM_001276378.2	RefSeq	NP_001263307.1	9	Standard
NM_001276379.2	RefSeq	NP_001263308.1	9	Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / Model	Organism	Observed Phenotype
lztfl1	Danio rerio	Structure: whole organism Quality: viability abnormal

Gene / Model

Organism

Observed Phenotype

lztfl1

Danio rerio

Structure: whole organism

Quality: viability

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

BBSome-mediated cargo-targeting to cilium
Cargo trafficking to the periciliary membrane
Cilium Assembly
Organelle biogenesis and maintenance

Biological Process

negative regulation of protein localization to cilium
negative regulation of protein localization to ciliary membrane

Molecular Function

protein binding
identical protein binding
protein-containing complex binding

Cellular Component

cytosol

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000296135
Coding exons: 10
Length: 92727
Individuals with no LoFs: 125734
Homozygous LoFs: 0
Heterozygous LoFs: 13
Defined: 125747
p: 0.0000517

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	1.65	89	145	0.614	0.00000683	1963
Missense (PolyPhen)		14	35.396	0.39552		541
Synonymous	1.18	42	52.9	0.793	0.00000251	528
Loss of Function	2.98	6	20.6	0.291	0.00000111	250

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.000062	0.000058	rare
Ashkenazi Jewish	0.00010	0.000099	rare
East Asian	0.000054	0.000054	rare
Finnish	0	0.0	absent
European (Non-Finnish)	0.000018	0.000018	rare
South Asian	0.00020	0.00020	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Regulates ciliary localization of the BBSome complex. Together with the BBSome complex, controls SMO ciliary trafficking and contributes to the sonic hedgehog (SHH) pathway regulation. May play a role in neurite outgrowth. May have tumor suppressor function. {ECO:0000269|PubMed:20233871, ECO:0000269|PubMed:22072986, ECO:0000269|PubMed:22510444}.;
Disease: DISEASE: Bardet-Biedl syndrome 17 (BBS17) [MIM:615994]: A syndrome characterized by usually severe pigmentary retinopathy, early- onset obesity, polydactyly, hypogenitalism, renal malformation and mental retardation. Secondary features include diabetes mellitus, hypertension and congenital heart disease. Bardet-Biedl syndrome inheritance is autosomal recessive, but three mutated alleles (two at one locus, and a third at a second locus) may be required for clinical manifestation of some forms of the disease. {ECO:0000269|PubMed:22510444, ECO:0000269|PubMed:23692385}. Note=The disease is caused by mutations affecting the gene represented in this entry. Patients carrying LZTFL1 mutations manifest mesoaxial polydactyly, a clinical feature very uncommon for Bardet-Biedl syndrome (PubMed:22510444 and PubMed:23692385). Some patients manifest situs inversus (PubMed:22510444). {ECO:0000269|PubMed:22510444}.;

Recessive Scores

pRec: 0.101

Intolerance Scores

LoFtool: 0.619
RVIS EVS: 0.5
RVIS percentile EVS: 79.89

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: E
Indispensability score: 0.881

Gene Damage Prediction

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