Abstract
BackgroundCongenital insensitivity to pain with anhidrosis (CIPA) is a rare autosomal recessive genetic disease characterized by the lack of reaction to noxious stimuli and anhidrosis. It is caused by mutations in the NTRK1 gene, which encodes the high affinity tyrosine kinase receptor I for Neurotrophic Growth Factor (NGF).Case PresentationWe present the case of a female patient diagnosed with CIPA at the age of 8 months. The patient is currently 6 years old and her psychomotor development conforms to her age (RMN, SPECT and psychological study are in the range of normality). PCR amplification of DNA, followed by direct sequencing, was used to investigate the presence of NTRK1 gene mutations. Reverse transcriptase (RT)-PCR amplification of RNA, followed by cloning and sequencing of isolated RT-PCR products was used to characterize the effect of the mutations on NTRK1 mRNA splicing. The clinical diagnosis of CIPA was confirmed by the detection of two splice-site mutations in NTRK1, revealing that the patient was a compound heterozygote at this gene. One of these alterations, c.574+1G>A, is located at the splice donor site of intron 5. We also found a second mutation, c.2206-2 A>G, not previously reported in the literature, which is located at the splice acceptor site of intron 16. Each parent was confirmed to be a carrier for one of the mutations by DNA sequencing analysis. It has been proposed that the c.574+1G>A mutation would cause exon 5 skipping during NTRK1 mRNA splicing. We could confirm this prediction and, more importantly, we provide evidence that the novel c.2206-2A>G mutation also disrupts normal NTRK1 splicing, leading to the use of an alternative splice acceptor site within exon 17. As a consequence, this mutation would result in the production of a mutant NTRK1 protein with a seven aminoacid in-frame deletion in its tyrosine kinase domain.ConclusionsWe present the first description of a CIPA-associated NTRK1 mutation causing a short interstitial deletion in the tyrosine kinase domain of the receptor. The possible phenotypical implications of this mutation are discussed.
Highlights
Congenital insensitivity to pain with anhidrosis (CIPA) is a rare autosomal recessive genetic disease characterized by the lack of reaction to noxious stimuli and anhidrosis
We present the first description of a CIPA-associated NTRK1 mutation causing a short interstitial deletion in the tyrosine kinase domain of the receptor
The NTRK1 gene is located on chromosome 1 (1q21-q22), is divided into 17 exons, and encodes the high affinity tyrosine kinase receptor I for Neurotrophic Growth Factor (NGF) [7], which is responsible for the correct differentiation and survival of sympathetic ganglion and nociceptive sensory neurons [8,9]
Summary
Congenital Insensitivity to Pain with Anhidrosis (CIPA; OMIM #256800), called Hereditary Sensory and Autonomic Neuropathy IV (HSAN IV), is an autosomal recessive disorder, part of a group of rare genetic neuropathies that affect the peripheral nervous system. To the best of our knowledge, these splice-site mutations in NTRK1 gene have not been previously described in patients with CIPA, a different change affecting the first nucleotide of IVS 5 (c.574+1G>A) has been reported in an earlier study [12]. We hypothesized that an alteration of the normal splicing caused by the IVS mutations would result in a mixture of differently sized amplified products To evaluate this possibility, PCR amplification products obtained with primer sets P1-F/P1-R and P2F/P2-R were cloned into the pCR2.1-TOPO vector. The second mutation identified in our patient (c.2206-2A>G) disrupts the 3’splice site of IVS 16, and results in the production of two different abnormally spliced mRNA variants, one showing partial retention of IVS16, and the other one showing partial deletion of exon 17, which may be due, as previously suggested, to the activation of cryptic splice sites [6]. It is not possible to establish to what extent the normal development of the CIPA patient described here is related to the nature of the NTRK1 mutations identified, to her early diagnosis, or to a combination of both factors
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