Homozygous mutations in NTRK1 gene underlie congenital insensitivity to pain with anhidrosis in Pakistani families

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. Neurology Asia 2016; 21(2) : 129 – 136 Address correspondence to: Muhammad Jawad Hassan PhD, Assistant Professor Healthcare Biotechnology, Atta ur Rahman School of Applied Biosciences (ASAB), National University of Sciences & Technology (NUST), Sector H-12, Islamabad, 44000, Pakistan. Tel: +92 51 9085-6135, Email: [email protected] INTRODUCTION Congenital insensitivity to pain with anhidrosis (CIPA; OMIM #256800), also designated as hereditary sensory and autonomic neuropathy IV (HSAN IV), is a rare autosomal recessive disorder which manifests during the first month of life. Fundamental characteristics includes loss of pain sensation, mainly in extremities and tongue, thermal sensation defects, self-mutilating behavior and intellectual disability. The selfmutilating behavior is mainly pertaining to orofacial tissues and manifests as premature loss of teeth, numerous other dental anomalies, various ulcers of oral tissues, tongue injuries, and scare formation. Insensitivity to pain results from the degeneration/absence of primary afferent fibers; while loss of sweating (anhidrosis) is due to loss of sympathetic postganglionic neurons. Anhidrosis often presents as recurrent attacks of unexplained fever and can have serious impacts. Sweat glands in CIPA patients were morphologically intact in number and structure, but were devoid of innervating nerve fibers. CIPA is caused by mutations of the NTRK1 gene (OMIM # 191315), or called as TRKA 6-10 which maps to chromosome 1 (1q21-q22). It comprises of 17 coding exons (Ensembl gene identifier-ENSG00000198400] and responsible to encode the highly active enzyme tyrosine Neurology Asia June 2016 130 kinase receptor I for Neurotrophic Growth Factor (NGF) domain. NGF is essential for the precise differentiation and maintenance of sympathetic ganglia and nociceptive sensory neurons. To date, more than 73 mutations are documented including 31 missense and 12 non-sense mutations (HMGD professional 2015.2) in different ethnic groups worldwide being more predominant and frequent in Asian population. The present study describes one novel (p.Y681X) and one previously described (p.P695L) mutation of NTRK1 gene in two Pakistani consanguineous families with CIPA. The p.P695L mutation was earlier documented in a Northern Israeli Bedouin family. In silico studies predicted the damaging effect of these mutations on protein structure and function. This is the first report of clinical and genetic evaluation of CIPA families from the Pakistani population.