1.Homozygous mutations in NTRK1 gene underlie congenital insensitivity to pain with anhidrosis in Pakistani families
Humaira Aziz Sawal ; Muhammad Ikram Ullah ; Arsalan Ahmad ; Abdul Nasir ; Ali Amar ; Ejaz A. Khan ; Mamoon Rashid ; Saqib Mahmood ; Peter John ; Wasim Ahmad ; Christian A. Hübner ; Muhammad Jawad Hassan
Neurology Asia 2016;21(2):129-136
Congenital insensitivity to pain with anhidrosis is a rare autosomal recessive disorder presenting
with loss of pain sensation, thermal sensation defects, and self-mutilating behavior. In the present
study, we recruited two consanguineous pedigree showing pain insensitivity symptoms from Pakistan
for clinical and molecular investigations. In family A, one female patient displayed classical CIPA
symptoms along with microcephaly and severe intellectual disability. During course of the disease,
her right foot was amputated and had remarkable dental degeneration and teeth shedding. In family B,
one boy presented with classical symptoms of congenital insensitivity to pain with anhidrosis. Blood
was collected from both families for molecular studies. Sequencing with the Ilumina Trusight One
Sequencing Panel covering 4813 OMIM genes revealed a known homozygous mutation c.2084C>T;
p.P695L of NTRK1 in family A and a novel truncated mutation c.2025C>G; p.Y681X in family B.
Protein modeling analysis of both mutations (p.P695L and p.Y681X) predicted loss of the rigidity in
tyrosine kinase domain of NTRK1 that led to conformational changes as well as deleterious effect on
protein function. The known mutation was reported more than a decade ago in a family from Northern
Israel and other non-sense mutation is newly identified. It is interested that most of NTRK1 mutations
are associated with this domain. This is first ever report of NTRK1 variants in congenital insensitivity
to pain with anhidrosis patients from Pakistan.
Pain Insensitivity, Congenital
Result Analysis
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