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Relevance to Autism

A rare mutation in the TMLHE gene has been identified with autism (Celestino-Soper et al., 2011). In a follow-up study, TMLHE deficiency caused by deletion of exon 2 was shown to be 2.82-fold more frequent in probands from male-male multiplex autism families compared with controls (7 in 909 compared to 24 in 8787; P = 0.023) (Celestino-Soper et al., 2012). Additionally, six of seven autistic male siblings of probands in male-male multiplex families had the deletion, suggesting that TMLHE deficiency is a risk factor for autism (meta-analysis Z-score = 2.90 and P = 0.0037), although with low penetrance (2-4%). These data suggest that dysregulation of carnitine metabolism may be important in nondysmorphic autism; that abnormalities of carnitine intake, loss, transport, or synthesis may be important in a larger fraction of nondysmorphic autism cases; and that the carnitine pathway may provide a novel target for therapy or prevention of autism.

Molecular Function

This gene encodes the protein trimethyllysine dioxygenase which is the first enzyme in the carnitine biosynthesis pathway. Carnitine plays an essential role in the transport of activated fatty acids across the inner mitochondrial membrane. The encoded protein converts trimethyllysine into hydroxytrimethyllysine.

External Links

        

References

Type
Title
Type of Disorder
Associated Disorders
Author, Year
Primary
Use of array CGH to detect exonic copy number variants throughout the genome in autism families detects a novel deletion in TMLHE.
ASD
Support
Rare complete knockouts in humans: population distribution and significant role in autism spectrum disorders.
ASD
Support
A common X-linked inborn error of carnitine biosynthesis may be a risk factor for nondysmorphic autism.
ASD
Recent Recommendation
Improvement of regressive autism symptoms in a child with TMLHE deficiency following carnitine supplementation.
ASD
Developmental regression
Recent Recommendation
Analysis of the chromosome X exome in patients with autism spectrum disorders identified novel candidate genes, including TMLHE.
ASD
ID

Rare

Variant ID
Variant Type
Allele Change
Residue Change
Inheritance Pattern
Inheritance Association
Family Type
Author, Year
 GEN269R001 
 copy_number_loss 
  
  
 Familial 
 Maternal 
 Simplex 
 GEN269R002 
 missense_variant 
 c.209G>A 
 p.Arg70His 
 Familial 
 Maternal 
 Simplex 
 GEN269R003 
 missense_variant 
 c.859G>A 
 p.Glu287Lys 
 Familial 
 Maternal 
 Simplex 
 GEN269R004 
 missense_variant 
 c.1045G>T 
 p.Val349Phe 
 Unknown 
  
 Simplex 
 GEN269R005 
 stop_gained 
 c.229C>T 
 p.Arg77Ter 
 Familial 
 Maternal 
 Multiplex 
 GEN269R006 
 missense_variant 
 c.730G>C 
 p.Asp244His 
 Familial 
 Maternal 
 Simplex 
 GEN269R007 
 missense_variant 
 c.1107G>T 
 p.Glu369Asp 
 Familial 
 Maternal 
 Simplex 
 GEN269R008 
 splice_site_variant 
 c.359-2A>G 
  
 Unknown 
  
 Unknown 
 GEN269R009 
 frameshift_variant 
 c.961_962del 
 p.Ile321LeufsTer5 
 Familial 
 Maternal 
 Simplex 

Common

Variant ID
Polymorphism
SNP ID
Allele Change
Residue Change
Population Origin
Population Stage
Author, Year
 GEN269C001 
 copy_number_loss 
  
  
  
 Multiplex families from AGRE and other sources 
 Discovery 
Chromosome
CNV Locus
CNV Type
# of studies
Animal Model
X
Deletion
 1
 
X
Duplication
 1
 
X
Deletion-Duplication
 18
 
X
Deletion
 2
 
X
Deletion
 1
 
X
Deletion
 1
 
X
Deletion-Duplication
 1
 
X
Deletion
 2
 
X
Deletion-Duplication
 1
 
X
Deletion
 7
 
X
Deletion-Duplication
 65
 

No Animal Model Data Available


Interactor Symbol Interactor Name Interactor Organism Entrez ID Uniprot ID Interaction Type Evidence Reference
CHD8 chromodomain helicase DNA binding protein 8 57680 Q9HCK8 ChIP-chip
Subtil-Rodrguez A , et al. 2013
STIM2 stromal interaction molecule 2 57620 A6H8L7 IP; LC-MS/MS
Huttlin EL , et al. 2015
UBC ubiquitin C 7316 P63279 Peptide fractionation; MS
Wagner SA , et al. 2011
Tmlhe trimethyllysine hydroxylase, epsilon 170898 Q91ZW6 Size-exclusion chromatography (SEC)
Vaz FM , et al. 2001

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