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Relevance to Autism

KLF7 has been proposed to be a possible candidate gene for phenotypes associated with 2q33.3-q34 deletions, incuding autism spectrum disorder/autistic features (Courtens et al., 1997; Pescucci et al., 2003; Bisgaard et al., 2006; Brandau et al., 2008; Rosenfeld et al., 2010; Jang et al., 2015). Powis et al., 2017 reported 4 unrelated individuals with de novo and potentially damaging missense variants in the KLF7 gene who shared similar clinical features, including developmental delay/intellectual disability, hypotonia, feeding/swallowing issues, psychiatric features, and neuromuscular symptoms; one of these individuals was also diagnosed with autism spectrum disorder. Additional rare de novo non-coding variants in this gene have been observed in ASD probands (Yuen et al., 2016; Yuen et al., 2017; Turner et al., 2017). Tian et al., 2022 reported that klf7 +/- mice exhibited a number of ASD-related behaviors, including deficits in social interaction and repetitive behavior.

Molecular Function

The protein encoded by this gene is a member of the Kruppel-like transcriptional regulator family. Members in this family regulate cell proliferation, differentiation and survival and contain three C2H2 zinc fingers at the C-terminus that mediate binding to GC-rich sites. This protein may contribute to the progression of type 2 diabetes by inhibiting insulin expression and secretion in pancreatic beta-cells and by deregulating adipocytokine secretion in adipocytes. This protein also plays a critical role in neuronal morphogenesis and the survival of sensory neurons.

External Links

        

References

Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
De novo variants in KLF7 are a potential novel cause of developmental delay/intellectual disability
DD, ID
ASD, ADD
Support
Autistic and dysmorphic features associated with a submicroscopic 2q33.3-q34 interstitial deletion detected by array comparative genomic hybridization
DD, ID, epilepsy/seizures
Autistic behavior
Support
Integrating de novo and inherited variants in 42
ASD
Support
Additional chromosomal abnormalities in patients with a previously detected abnormal karyotype, mental retardation, and dysmorphic features
DD, ID
Autistic features
Support
Genomic Patterns of De Novo Mutation in Simplex Autism
ASD
Support
Chromosome 2 deletion encompassing the MAP2 gene in a patient with autism and Rett-like features.
DD, epilepsy/seizures
Autistic features, stereotypy
Support
Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder
ASD
Support
Genome-wide characteristics of de novo mutations in autism
ASD
Support
Interstitial deletion 2q33.3-q34 in a boy with a phenotype resembling the Seckel syndrome
DD, ID
Support
Autistic and Rett-like features associated with 2q33.3-q34 interstitial deletion
DD, ID
Autistic features, stereotypy
Support
Copy number variations associated with autism spectrum disorders contribute to a spectrum of neurodevelopmental disorders.
ASD
Recent Recommendation
Krüppel-like Transcription Factor 7 Is a Causal Gene in Autism Development
ASD
Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
 GEN1311R001 
 copy_number_loss 
  
  
 De novo 
  
  
 GEN1311R002 
 copy_number_loss 
  
  
 De novo 
  
  
 GEN1311R003 
 copy_number_loss 
  
  
 De novo 
  
  
 GEN1311R004 
 copy_number_loss 
  
  
 De novo 
  
  
 GEN1311R005 
 copy_number_loss 
  
  
 Unknown 
  
  
 GEN1311R006 
 copy_number_loss 
  
  
 De novo 
  
 Simplex 
 GEN1311R007 
 missense_variant 
 c.410C>T 
 p.Thr137Met 
 De novo 
  
 Simplex 
 GEN1311R008 
 missense_variant 
 c.790G>A 
 p.Asp264Asn 
 De novo 
  
 Simplex 
 GEN1311R009 
 missense_variant 
 c.415C>T 
 p.Pro139Ser 
 De novo 
  
 Simplex 
 GEN1311R010 
 missense_variant 
 c.410C>T 
 p.Thr137Met 
 De novo 
  
 Simplex 
 GEN1311R011 
 intron_variant 
 n.515-11604G>A 
  
 De novo 
  
 Simplex 
 GEN1311R012 
 intron_variant 
 c.103-10377_103-10367del 
  
 De novo 
  
 Simplex 
 GEN1311R013 
 intron_variant 
 c.531+4993_531+4995del 
  
 De novo 
  
 Multiplex 
 GEN1311R014 
 intron_variant 
 n.576-4471G>A 
  
 De novo 
  
 Simplex 
 GEN1311R015 
 intron_variant 
 n.575+7470G>T 
  
 De novo 
  
 Simplex 
 GEN1311R016 
 3_prime_UTR_variant 
 c.*1606C>T 
  
 De novo 
  
 Simplex 
 GEN1311R017 
 intron_variant 
 n.575+4675G>A 
  
 De novo 
  
 Simplex 
 GEN1311R018 
 missense_variant 
 c.424C>G 
 p.Pro142Ala 
 De novo 
  
  
Chromosome
CNV Locus
CNV Type
# of studies
Animal Model
2
Duplication
 1
 
2
Duplication
 2
 
2
Duplication
 1
 
2
Duplication
 2
 
2
Deletion
 3
 
2
Deletion
 1
 
2
Deletion-Duplication
 10
 
2
Deletion
 3
 

Model Summary

Klf7 mutant mice displayed abnormal growth, deficits in social interaction, learning and memory, and increased repetitive behavior, but normal olfaction. 631 ASD risk genes are differentially expressed in Klf7 mutant mice. Specifically, Klf7 homozygous mutant mice displayed high mortality of 90% within the first two months, and had severely hypoplastic olfactory bulbs and smaller brains after birth. Mice restored with adeno-associated virus (AAV)-mediated overexpression of Klf7 exhibit restored social interaction and self-grooming behaviors.

References

Type
Title
Author, Year
Primary
Krüppel-like Transcription Factor 7 Is a Causal Gene in Autism Development
Model Type: Genetic
Model Genotype: Heterozygous
Mutation: Klf7 conditional ready mice were generated using CRISPR/Cas9 nuclease technology to add loxP sites flanking exon 2. Conditional knockouts were generated by crossing conditional ready mice to mice carrying a Nestin-Cre transgene, resulting in the deletion of exon 2 in neurons, which express Nestin. Mice were kept in a C57BL/6J background.
Allele Type: conditional knockout
Strain of Origin:
Genetic Background: C57BL/6J
ES Cell Line:
Mutant ES Cell Line:
Model Source: Cyagen Biosciences Inc.
Category
Entity
Quantity
Experimental Paradigm
Age at Testing
General locomotor activity: ambulatory activity1
Increased
 Open field test
 5-6 months
Self grooming1
Increased
 Grooming behavior assessments
 5-6 months
Seizures1
Increased
 Observation of seizures
 4-12 months
Social memory1
Decreased
 Three-chamber social approach test
 5-6 months
Social approach1
Decreased
 Three-chamber social approach test
 5-6 months
Nest building behavior1
Decreased
 Nest building assay
 5-6 months
Size/growth1
Decreased
 General observations
 1 month
Spatial reference memory1
Decreased
 Morris water maze test
 5-6 months
Spatial learning1
Decreased
 Morris water maze test
 5-6 months
Spatial working memory1
Decreased
 Y-maze test
 5-6 months
Gene expression1
Decreased
 Quantitative PCR (qRT-PCR)
 1 month
Differential gene expression1
Abnormal
 RNA sequencing
 1 month
Targeted expression1
Decreased
 Quantitative PCR (qRT-PCR)
 unreported
Exploratory activity1
 No change
 Three-chamber social approach test
 5-6 months
Object recognition memory1
 No change
 Novel object recognition test
 5-6 months
Brain size1
 No change
 Measurement of tissue weight
 0-2 months
Olfaction1
 No change
 Buried food test
 5-6 months
Olfaction1
 No change
 Three-chamber social approach test
 5-6 months
 Not Reported:

 

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