We 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.
CONCLUSIONS: 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 possible phenotypical implications of this mutation are discussed.