Haploinsufficiency of the nerve growth factor beta gene in a 1p13 deleted female child with an insensitivity to pain

Abstract

Pain insensitivity is mediated at the genetic level by the disruption of specific genes associated with neuronal development. Mammalian in vivo and in vitro studies have shown the nerve growth factor (NGF) gene to play an integral role in nerve maintenance and function. Pain insensitivity in humans can be attributed to hereditary sensory and autonomic neuropathies (HSAN) of which there are five classes (HSAN I – HSAN V). The human nerve growth factor beta gene (NGFB) located on chromosome 1p13.2 has been found to cause HSAN V within individuals homozygous for a point mutation in NGFB. Although heterozygotes can display a milder phenotype, this has only been observed in adults. We report a karyotypically normal 5‐year‐old female with developmental delay, mild facial dysmorphism, and unsteady gait. Pain and thermal insensitivity were noted as were recurrent mouth ulcers, facial flushing, recurrent episodes of increased body temperature and unexplained sweating, indicative of a sensory neuropathy with mild autonomic involvement. Array comparative genomic hybridization (aCGH) analysis revealed a de‐novo deletion within chromosome 1p13 of the child involving the NGFB gene. Sequence analysis of the homologous NGFB gene identified no mutation, implying that sensory neuropathy was caused by haploinsufficiency of the NGFB gene.

From genes to pain: nerve growth factor and hereditary sensory and autonomic neuropathy type V

“…A study performed on a large cohort of HSAN patients from UK revealed that two out of 140 subjects had a phenotype that could be ascribed to HSAN V, and were carriers of a duplication or mutation (p.Ser187Asn) in the NGFB gene, the pathogenicity of which is still to be demonstrated (Davidson et al ., ). The attribution to HSAN V to a case described in the UK, in which a deletion within the chromosome 1p13 determined an haploinsufficiency of the NGFB gene (Fitzgibbon et al ., ), is also controversial.…”

Nerve growth factor β polypeptide (NGFB) genetic variability: association with the methadone dose required for effective maintenance treatment

“…Animal studies demonstrated that BDNF regulates the mesolimbic dopamine pathway and is involved in the response to aversive social experiences 17. There are only a few studies of the effect of NGFB genetic variability in humans, mostly related to insensitivity to pain 18–2021.…”

1p13.2 deletion displays clinical features overlapping Noonan syndrome, likely related to NRAS gene haploinsufficiency

“…Isolated chromosome 1p13.2 microdeletions are not common; we could find only three individuals reported in the literature (Mattia et al ., 1992; Bisgaard et al ., 2007; Fitzgibbon et al ., 2009). Additionally, six patients with isolated deletions partially overlapping the one of our patient had been reported previously in DECIPHER database.…”

“…We concluded that the clinical characteristics of the patient could be attributed to the 1p13.2 haploinsufficiency. Additionally, we compared his clinical characteristics with the phenotype of six patients with similar deletions overlapping the one of our patient reported previously in DECIPHER database and three individuals reported in the literature (Mattia et al ., 1992; Bisgaard et al ., 2007; Fitzgibbon et al ., 2009). On these bases we propose that haploinsufficiency of NRAS gene (OMIM *164790) may be important in determining the clinical phenotype of this microdeletion.…”