Congenital insensitivity to pain with anhidrosis (CIPA): Novel mutations of theTRKA (NTRK1) gene, a putative uniparental disomy, and a linkage of the mutantTRKA andPKLR genes in a family with CIPA and pyruvate kinase deficiency

Abstract

Congenital insensitivity to pain with anhidrosis is an autosomal recessive hereditary disorder characterized by recurrent episodic fever, anhidrosis (inability to sweat), absence of reaction to noxious stimuli, self-mutilating behavior, and mental retardation. The human TRKA gene (NTRK1), located on chromosome 1q21-q22 encodes the receptor tyrosine kinase for nerve growth factor. We reported that TRKA is the gene responsible for CIPA and we developed a comprehensive strategy to screen for TRKA mutations and polymorphisms, as based on the gene's structure and organization. Here we report eight novel mutations detected as either a homozygous or heterozygous state in nine CIPA families from five countries. Mendelian inheritance of the mutations was confirmed in seven families for which samples from either parent were available. However, non-mendelian inheritance seems likely for the family when only samples from the mother and siblings, (but not from the father) were available. A paternal uniparental disomy for chromosome 1 is likely to be the cause of reduction to homozygosity of the TRKA gene mutation in this family. Interestingly, a Hispanic patient from the USA has two autosomal genetic disorders, CIPA and pyruvate kinase deficiency, whose genetic loci are both mapped to a closely linked chromosomal region. A splice mutation and a missense mutation were detected in the TRKA and PKLR genes from the homozygous proband, respectively. Thus, concomitant occurrence of two disorders is ascribed to a combination of two separate mutant genes, not a contiguous gene syndrome. This finding suggests a mechanism responsible for two autosomal genetic disorders in one patient. All these data further support findings that TRKA defects can cause CIPA in various ethnic groups. This will aid in diagnosis and genetic counseling of this painless but severe genetic disorder.

A GOG 210 aCGH study of gain at 1q23 in endometrioid endometrial cancer in the context of racial disparity and outcome

“…The NTKR1 gene encodes the neurotrophic tyrosine kinase-1 receptor and belongs to a family of nerve growth factor receptors whose ligands include neurotrophins. Mutations in the NTKR1 gene have been associated with a rare congenital insensitivity to (Indo et al, 2001). Much more common is intrachromosomal rearrangement or translocation of the NTKR1 gene in papillary thyroid carcinoma (Brzeziań ska et al, 2007) arising from the fusion of the 3 0 terminal sequences of the NTRK1 with 5 0 terminal sequences of Figure 4.…”

An Infant With Primary Tooth Loss and Palmar Hyperkeratosis: A Novel Mutation in the NTRK1 Gene Causing Congenital Insensitivity to Pain With Anhidrosis

“…6 In addition, there are several reports of children with CIPA who bit off a portion of their tongue or pulled out their own teeth. [15][16][17] Health care maintenance issues are important for children with CIPA: Rosemberg et al 18 reported that an estimated 20% die from hyperpyrexia in the first 3 years of life, while Shorer et al 12 report sepsis leading to death in 23% of their CIPA patients. However, other groups have not reported similar mortality rates.…”

Fumarase deficiency caused by homozygous P131R mutation and paternal partial isodisomy of chromosome 1

“…Maternal UPD has been reported in Herlitz junctional epidermolysis bullosa [Pulkkinen et al, 1997;Takizawa et al, 1998], insulin-dependent diabetes mellitus [Field et al, 1998], developmental delay [Rothlisberger et al, 2001], and ChediakHigashi syndrome [Dufourcq-Lagelouse et al, 1999]. Paternal UPD has been described in pycnodysostosis [Gelb et al, 1998], Herlitz junctional epidermolysis bullosa [Takizawa et al, 1998[Takizawa et al, , 2000, retinitis pigmentosa [Rivolta et al, 2002], retinal dystrophy [Thompson et al, 2002] and congenital insensitivity to pain with anhidrosis [Miura et al, 2000;Indo et al, 2001]. UPD can be complete isodisomy [Dufourcq-Lagelouse et al, 1999;Miura et al, 2000], or partial isodisomy [Rivolta et al, 2002], with or without heterodisomy.…”