This is the first case description of an individual with a homozygous deletion of the TNR gene. Our patient's phenotype was characterised by global developmental delay, cognitive deficit, transient hyperkinetic movement disorder (opisthotonic posturing and choreoathetosis), central hypotonia and peripheral spasticity. Sequencing TNR in 219 patients with idiopathic ID failed to identify any potential pathogenic mutation, indicating that TNR disruption represents a rare cause of ID. Additional screening of families with ID would be needed to determine the frequency of TNR pathogenic mutations in recessive ID.
Deletions encompassing
TNR are extremely rare. Among 38 750 probands tested at Signature Genomics Laboratories, only eight large heterozygous deletions (>5 Mb) that involved
TNR along with other genes were detected, and there were no smaller deletions found. The Database of Genomic Variants (
http://projects.tcag.ca/variation/) reports three heterozygous deletions encompassing the 3′ end of
TNR (3/66741, frequency 4.5×10
−5), and there are no exonic deletions in
TNR among 2026 control probands in the CNV CHOP database (
http://www.cnv.chop.edu). There are no reports of any homozygous deletions of
TNR.
Although the deletion in our proband contained in addition to
TNR, part of a second gene,
KIAA0040, the deletion of
TNR is most likely responsible for the phenotype.
KIAA0040 encodes a protein whose exact function is currently unknown and whose protein expression was recently detected in colorectal cancer cells.
9 Microarray expression experiments suggest that
KIAA0040 has little to no expression in the central nervous system making its implication in our patient's pathology unlikely (data from HUGE (
http://www.kazusa.or.jp/huge/), Gene Report BioGPS (
http://www.biogps.org/), UCSC Genome Browser (
http://www.genome.ucsc.edu/)). On the other hand,
TNR encodes tenascin-R, an extracellular matrix protein that is expressed mainly in the central nervous system. TNR plays a role in the regulation of neurite outgrowth, neural cell adhesion and cell survival.
5 TNR expression is tightly spatiotemporally regulated, especially during the formation of the cortical plate.
10 It is produced abundantly by oligodendrocytes and their precursors, and clusters around myelinated axons, particularly around nodes of Ranvier. When myelination is completed, TNR expression decreases with residual expression in a subset of motoneurons and interneurons of the cortex, hippocampus, cerebellum, retina, brainstem and spinal cord. TNR is an important constituent of the perineural nets surrounding inhibitory interneurons.
11–13Homozygous
TNR knock-out mice are viable and fertile but show motor and cerebellar abnormalities with deficits in the rota rod testing.
13 Behavioural testing reveals severe cognitive deficits, with alteration in associative learning and spatial representation.
3 Although gross anatomy and histology are normal, perineuronal nets associated with parvalbumin-expressing GABAergic neurons, which have a role in the regulation of interneuronal excitability, are significantly less developed.
13
14 In vitro assays of
TNR-null hippocampal slices indicate impaired synaptic plasticity with significant defects of long-term potentiation that may underlie the observed impairment in learning and memory.
15The global developmental delay observed in our patient with the homozygous TNR deletion is consistent with a broad dysfunction of learning and memory. Although the opisthotonic posturing and choreaoathetosis observed in our patient have not been described in animal models, it is conceivable that they may be related to deficits in perineural inhibition, especially at the level of the spinal cord and basal ganglia.
In summary, our study reports for the first time a complete loss of TNR in a patient with ID. This observation has implications for our understanding of mechanisms of learning and memory in humans.
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