Complete paternal uniparental isodisomy for chromosome 1 revealed by mutation analyses of the TRKA (NTRK1) gene encoding a receptor tyrosine kinase for nerve growth factor in a patient with congenital insensitivity to pain with anhidrosis

Abstract

Uniparental disomy (UPD) is defined as the presence of a chromosome pair that derives from only one parent in a diploid individual. The human TRKA gene on chromosome 1q21-q22 encodes a receptor tyrosine kinase for nerve growth factor and is responsible for an autosomal recessive genetic disorder: congenital insensitivity to pain with anhidrosis (CIPA). We report here the second case of paternal UPD for chromosome 1 in a male patient with CIPA who developed normally at term and did not show overt dysmorphisms or malformations. He had only the usual features of CIPA with a homozygous mutation at the TRKA locus and a normal karyotype with no visible deletions or evidence of monosomy 1. Haplotype analysis of the TRKA locus and allelotype analyses of whole chromosome 1 revealed that the chromosome pair was exclusively derived from his father. Non-maternity was excluded by analyses of autosomes other than chromosome 1. Thus, we have identified a complete paternal isodisomy for chromosome 1 as the cause of reduction to homozygosity of the TRKA gene mutation, leading to CIPA. Our findings further support the idea that there are no paternally imprinted genes on chromosome 1 with a major effect on phenotype. UPD must be considered as a rare but possible cause of autosomal recessive disorders when conducting genetic testing.

The biopsychosocial approach to chronic pain: Scientific advances and future directions.

“…A combined defect in sensory and autonomic neurons derived from the neural crest A reduced evoked potential (Chatrian, Farrell, Canfield, & Lettich, 1975;Shorey & Lobo, 1990) Lack of pain experience following electrical shock; (Manfredi et al, 1981) Self-mutilation and fractures (Itoh, Nakajima, Yagishita, Nakano, & Kawada, 1986;Chatrian et al, 1975;Matsuo, Kurokawa, Goya, & Ohta, 1981;Sweet, 1981;Derwin, Glover, & Wojtys, 1994;Nolano et al, 2000;Schulman et al, 2001) Lack of flare response to histamine injection (Manfredi et al, 1981;Nolano et al, 2000) Lack of temperature regulation (Itoh et al, 1986;Matsuo et al, 1981;Vital et al, 1998;Sztriha, Lestringant, Hertecant, Frossard, & Masouye, 2001) Overexpression of endogenous opioids (Dehen, Willer, Boureau, & Cambier, 1977;Dehen, Willer, Prier, Boureau, & Cambier, 1978) Reduced number of primary afferent nociceptors (Larner, Moss, Rossi, & Anderson, 1994) Loss of neurons in sympathetic ganglia (Dyck et al, 1983;Derwin et al, 1994;Shorer, Moses, Hershkovitz, Pinsk, & Levy, 2001;Sztriha et al, 2001) Loss of trkA function (receptor for nerve growth factor) as the result of mutations of the trkA receptor gene (Indo et al, 1996;Mardy et al, 1999;Yotsumoto et al, 1999;Shatzky et al, 2000;Toscano et al, 2000;Greco, Villa, Fusetti, Orlandi, & Pierotti, 2000;Miura et al, 2000a;Miura et al, 2000b;…”

The Role of Imprinted Genes in Fetal Growth

“…Two cases of paternal UPD1 showed an abnormal phenotype due to the expression of recessive conditions but without any additional features [25,26], thus suggesting that chromosome 1 has no imprinted genes with detectable effects on the phenotype.…”

Two cases of mosaic RhD blood-group phenotypes and paternal isodisomy for chromosome 1

“…They were found accidentally either through studies on rare autosomal recessive disorders, i.e., Herlitz junctional epidermolysis bullosa [Pulkkinen et al, 1997;Takizawa et al, 2000], pycnodysostosis [Gelb et al, 1998], Chediak-Higashi syndrome [Dufourcq-Lagelouse et al, 1999], congenital insensitivity to pain with anhidrosis [Miura et al, 2000], multiple congenital anomalies [Chen et al, 1999], or during a genome screening of families with insulin-dependent diabetes mellitus using polymorphic DNA markers [Field et al, 1998]. We would like to emphasize here that isodisomy 1 is not infrequent and also causes unusual Rh phenotypes.…”

“…UPD1 has been identi®ed in seven individuals [Pulkkinen et al, 1997;Field et al, 1998;Gelb et al, 1998;Dufourcq-Lagelouse et al, 1999;Chen et al, 1999;Miura et al, 2000;Takizawa et al, 2000]. They were found accidentally either through studies on rare autosomal recessive disorders, i.e., Herlitz junctional epidermolysis bullosa [Pulkkinen et al, 1997;Takizawa et al, 2000], pycnodysostosis [Gelb et al, 1998], Chediak-Higashi syndrome [Dufourcq-Lagelouse et al, 1999], congenital insensitivity to pain with anhidrosis [Miura et al, 2000], multiple congenital anomalies [Chen et al, 1999], or during a genome screening of families with insulin-dependent diabetes mellitus using polymorphic DNA markers [Field et al, 1998].…”

“…UPD in humans has been observed in all but chromosomes 3, 5, 12, 18, and 19 [Ledbetter and Engel, 1995;Benlian et al, 1996;Gelb et al, 1998]. There have been seven individuals reported with UPD for chromosome 1 (UPD1): those with maternal heterodisomy [Pulkkinen et al, 1997;Field et al, 1998], paternal heterodisomy [Gelb et al, 1998], maternal isodisomy [Dufourcq-Lagelouse et al, 1999], complete paternal isodisomy [Miura et al, 2000;Takizawa et al, 2000], and with paternal isodisomy for 1p/1q [Chen et al, 1999].…”