NGF – Hereditary Sensory and Autonomic Neuropathy

Hereditary sensory and autonomic neuropathies (HSAN) are rare disorders of peripheral neurons leading to insensitivity to pain and autonomic dysfunction. The nerve growth factor beta gene (NGF) encodes a key neurotrophin for survival and function of sensory and sympathetic neurons. Biallelic loss-of-function variants in NGF cause HSAN type V (MONDO:0015364) with congenital pain insensitivity, whereas haploinsufficiency may yield a milder phenotype in childhood.

Initial genetic evidence emerged from a single 5-year-old female with global developmental delay, unsteady gait, pain and thermal insensitivity, erythema and autonomic features, harboring a de novo deletion of the NGFB locus on chromosome 1p13 (1 proband) (PMID:19183217). A consanguineous Arab family displayed five affected homozygotes with a compound NGFB mutation c.[680C>A]+[681_682delGG] (5 probands), confirming autosomal recessive inheritance and segregation with disease (PMID:20978020). A single HSAN5 case carrying the furin-site variant c.361C>T (p.Arg121Trp) further supports loss-of-function as pathogenic (1 proband) (PMID:30296891).

Large cohort screenings indicate that NGF mutations are rare contributors to HSAN. In a UK series of 140 index patients, one carried NGFB c.560G>A (p.Ser187Asn) (1/140) (PMID:22302274), and an international CIP/HSAN study of 73 families uncovered additional novel NGF-associated variants, underscoring locus heterogeneity (PMID:37769650).

The NGF variant spectrum encompasses missense changes (e.g., c.680C>A (p.Thr227Lys)), nonsense alleles (e.g., c.241C>T (p.Arg81Ter)), frameshifts (c.681_682del (p.Ala228fs)), and larger deletions. No recurrent founder alleles have been described, and carrier frequencies remain to be defined.

Functional assays demonstrate that frameshift mutants (V232fs) fail to secrete mature NGFβ and cannot induce PC12 differentiation (PMID:20978020), while missense mutations in receptor-binding loops abrogate high-affinity TrkA and p75^NTR interactions (PMID:7890765, PMID:8868481). The HSAN5-associated R100W variant selectively disrupts p75^NTR binding with preserved TrkA signaling, elucidated by surface plasmon resonance and cellular assays (PMID:21387003, PMID:29108999).

A heterozygous knock-in mouse model bearing the human NGFR100W allele exhibits normal cognitive performance but impaired nociception, reduced intra-epidermal nerve fibers and disrupted pain signaling pathways, recapitulating the human HSAN V phenotype (PMID:31685654).

Collectively, genetic and experimental data support a Strong association between NGF and HSAN V, with autosomal recessive inheritance, clear segregation in affected families, and concordant in vitro and in vivo functional studies. Key take-home: NGF variant analysis informs diagnosis of HSAN V and guides gene-specific therapeutic strategies.

References

• Developmental medicine and child neurology • 2009 • Haploinsufficiency of the nerve growth factor beta gene in a 1p13 deleted female child with an insensitivity to pain. PMID:19183217
• Journal of medical genetics • 2011 • A novel NGF mutation clarifies the molecular mechanism and extends the phenotypic spectrum of the HSAN5 neuropathy. PMID:20978020
• Molecular pain • 2018 • A third HSAN5 mutation disrupts the nerve growth factor furin cleavage site. PMID:30296891
• Journal of neurology • 2012 • Frequency of mutations in the genes associated with hereditary sensory and autonomic neuropathy in a UK cohort. PMID:22302274
• Brain : a journal of neurology • 2023 • Genetic landscape of congenital insensitivity to pain and hereditary sensory and autonomic neuropathies. PMID:37769650
• Progress in neurobiology • 2020 • A missense point mutation in nerve growth factor (NGFR100W) results in selective peripheral sensory neuropathy. PMID:32693191
• The Journal of neuroscience : the official journal of the Society for Neuroscience • 2019 • The NGFR100W Mutation Specifically Impairs Nociception without Affecting Cognitive Performance in a Mouse Model of Hereditary Sensory and Autonomic Neuropathy Type V. PMID:31685654

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