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.
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.
Miura
Y
Y
Department of Pediatrics, Kumamoto University School of Medicine, Japan.
Hiura
M
M
Torigoe
K
K
Numata
O
O
Kuwahara
A
A
Matsunaga
M
M
Hasegawa
S
S
Boku
N
N
Ino
H
H
Mardy
S
S
Endo
F
F
Matsuda
I
I
Indo
Y
Y
D000483:Alleles; D000782:Aneuploidy; D002675:Child, Preschool; D002878:Chromosomes, Human, Pair 1; D005220:Fathers; D005260:Female; D006239:Haplotypes; D006801:Humans; D007007:Hypohidrosis / Q000235:genetics*; D008297:Male; D009154:Mutation; D000699:Pain Insensitivity, Congenital / Q000235:genetics*; D010375:Pedigree; D016133:Polymerase Chain Reaction; D020917:Receptor, trkA / Q000235:genetics*
D020917:Receptor, trkA