The phenotype of congenital insensitivity to pain due to the NaV1.9 variant p.L811P.
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ABSTRACT:
SUBMITTER: Woods CG
PROVIDER: S-EPMC4402639 | biostudies-literature | 2015 May
REPOSITORIES: biostudies-literature
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The phenotype of congenital insensitivity to pain due to the NaV1.9 variant p.L811P.
Woods Christopher Geoffrey CG Babiker Mohamed Osman Eltahir MO Horrocks Iain I Tolmie John J Kurth Ingo I
European journal of human genetics : EJHG 20140813 5
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Project description:BackgroundCongenital insensitivity to pain (CIP) and hereditary sensory and autonomic neuropathies (HSANs) are a rare group of genetic disorders causing inability to feel pain. Three different associated variants have been identified in dogs: 1 in Border Collies, 1 in mixed breed dogs, and 1 in Spaniels and Pointers.ObjectivesTo clinically and genetically characterize CIP in a family of mixed breed dogs.AnimalsTwo mixed breed dogs from the same litter were independently presented: 1 for evaluation of painless fractures, and the other for chronic thermal skin injuries.MethodsPhysical, neurological, and histopathological evaluations were performed. Whole genome sequencing of 1 affected dog was used to identify homozygous protein-changing variants that were not present in 926 control genomes from diverse dog breeds.ResultsPhysical and neurological examinations showed the absence of superficial and deep pain perception in the entire body. Histopathological evaluations of the brain, spinal cord and sensory ganglia were normal. Whole genome sequencing identified a homozygous missense variant in SCN9A, XM_038584713.1:c.2761C>T or XP_038440641.1:(p.Arg921Cys). Both affected dogs were homozygous for the mutant allele, which was not detected in 926 dogs of different breeds.Conclusions and clinical importanceWe confirmed the diagnosis of CIP in a family of mixed breed dogs and identified a likely pathogenic variant in the SCN9A gene. The clinical signs observed in these dogs mimic those reported in humans with pathogenic SCN9A variants causing CIP. This report is the first of a spontaneous pathogenic SCN9A variant in domestic animals.
| S-EPMC9889608 | biostudies-literature
Project description:Congenital insensitivity to pain with anhidrosis (CIPA), also called hereditary sensory and autonomic neuropathy type IV (HSAN-IV), is an extremely rare autosomal recessive disease. It is characterized by insensitivity to pain, inability to sweat, episodes of hyperpyrexia, and intellectual disability. These factors render the affected persons to repeatedly injure and traumatise themselves to the degree that they become disabled. No specific treatment to the moment, but it needs multidisciplinary approach, and certain life adaptations and education. Here we report 4 unrelated Sudanese children affected with this rare neurological disorder, to raise the awareness on this rare disease, reflecting its spectrum, and the challenges which patients and their families face, especially when living in a hot country.
| S-EPMC5237840 | biostudies-literature
Project description:Introduction or backgroundCongenital insensitivity to pain (CIP) is caused by extremely rare Mendelian genetic disorders. CIP individuals demonstrate the unexpectedly severe consequences of painlessness. Although only a small number of causative conditions and genes are known, most have led to profound insights into human nociception. CIP gene discovery is catalyzing the manufacture of completely new classes of analgesics, and these are needed as alternatives to synthetic highly potent opioids.Sources of dataPubmed.gov peer-reviewed journal articles and reviews.Areas of agreementThe importance of nerve growth factor-tropomyosin receptor kinase A (NGF-TRKA) signalling for nociceptor genesis and subsequent pain sensing.New analgesics can be generated from knowledge of the NGF-TRKA nociceptor pathway.Increased susceptibility to Staphylococcus aureus infection is a consequence of deficient NGF-TRKA signalling.Mutations in the voltage-gated sodium channels SCN9A and SCN11A can cause congenital painlessness, and in contradistinction, other mutations can cause episodic neuropathic pain. SCN9A/Nav1.7 is an analgesic target. SCN11A/Nav1.9 is unlikely to be an analgesic target.There are further Mendelian causes of painlessness to be discovered.Areas of controversyWhich NGF-TRKA intracellular signalling pathways operate in nociceptor development and which in post-natal pain sensing?Why have no clinically effective Nav1.7 antagonist been generated? SCN9A-CIP causes analgesia, at least in part, through endogenous opioids.Why do all CIP phenotypes involve a complete loss of all types of nociception?Areas timely for developing researchPRDM12 as an analgesic target.Discovery of the function and analgesic potential of new CIP genes.Can NGF-TRKA be used in the treatment of S. aureus?
| S-EPMC7227775 | biostudies-literature
Project description:Congenital insensitivity to pain with anhidrosis is a rare disease of the nervous system which causes one to lose his/her feeling of pain. The disease is subtype four of hereditary sensory and autonomic neuropathy (HSAN IV) that results from NTRK1 gene defect. Direct sequencing was performed to screen NTRK1 for mutations. The result revealed a homozygous deletion of adenine on intron 14 that may cause the disease.
| S-EPMC4202553 | biostudies-literature
Project description:ObjectiveMutations in SCN9A have been reported in (1) congenital insensitivity to pain (CIP); (2) primary erythromelalgia; (3) paroxysmal extreme pain disorder; (4) febrile seizures and recently (5) small fibre sensory neuropathy. We sought to investigate for SCN9A mutations in a clinically well-characterised cohort of patients with CIP and erythromelalgia.MethodsWe sequenced all exons of SCN9A in 19 clinically well-studied cases including 6 CIP and 13 erythromelalgia (9 with family history, 10 with small-fibre neuropathy). The identified variants were assessed in dbSNP135, 1K genome, NHLBI-Exome Sequencing Project (5400-exomes) databases, and 768 normal chromosomes.ResultsIn erythromelalgia case 7, we identified a novel Q10>K mutation. In CIP case 6, we identified a novel, de novo splicing mutation (IVS8-2A>G); this splicing mutation compounded with a nonsense mutation (R523>X) and abolished SCN9A mRNA expression almost completely compared with his unaffected father. In CIP case 5, we found a variant (P610>T) previously considered causal for erythromelalgia, supporting recently raised doubt on its causal nature. We also found a splicing junction variant (IVS24-7delGTTT) in all 19 patients, this splicing variant was previously considered casual for CIP, but IVS24-7delGTTT was in fact the major allele in Caucasian populations.ConclusionsTwo novel SCN9A mutations were identified, but frequently polymorphism variants are found which may provide susceptibility factors in pain modulation. CIP and erythromelalgia are defined as genetically heterogeneous, and some SCN9A variants previously considered causal may only be modifying factors.
| S-EPMC3594382 | biostudies-literature
Project description:Congenital insensitivity to pain (OMIM 243000) is an extremely rare disorder caused by loss-of-function mutations in SCN9A encoding Nav1.7. Although the SCN9A mutations and phenotypes of painlessness and anosmia/hyposmia in patients are previously well documented, the complex relationship between genotype and phenotype of congenital insensitivity to pain remains unclear. Here, we report a congenital insensitivity to pain patient with novel SCN9A mutations. Functional significance of novel SCN9A mutations was assessed in HEK293 cells expressing Nav1.7, the results showed that p.Arg99His significantly decreased current density and reduced total Nav1.7 protein levels, whereas p.Trp917Gly almost abolished Nav1.7 sodium current without affecting its protein expression. These revealed that mutations in Nav1.7 in this congenital insensitivity to pain patient still retained partial channel function, but the patient showed completely painlessness, the unexpected genotypic-phenotypic relationship of SCN9A mutations in our patient may challenge the previous findings "Nav1.7 total loss-of-function leads to painlessness." Additionally, these findings are helpful for understanding the critical amino acid for maintaining function of Nav1.7, thus contributing to the development of Nav1.7-targeted analgesics.
| S-EPMC7235659 | biostudies-literature
Project description:SCN9Aencodes the voltage-gated sodium channel Na(v)1.7, a protein highly expressed in pain-sensing neurons. Mutations in SCN9A cause three human pain disorders: bi-allelic loss of function mutations result in Channelopathy-associated Insensitivity to Pain (CIP), whereas activating mutations cause severe episodic pain in Paroxysmal Extreme Pain Disorder (PEPD) and Primary Erythermalgia (PE). To date, all mutations in SCN9A that cause a complete inability to experience pain are protein truncating and presumably lead to no protein being produced. Here, we describe the identification and functional characterization of two novel non-truncating mutations in families with CIP: a homozygously-inherited missense mutation found in a consanguineous Israeli Bedouin family (Na(v)1.7-R896Q) and a five amino acid in-frame deletion found in a sporadic compound heterozygote (Na(v)1.7-DeltaR1370-L1374). Both of these mutations map to the pore region of the Na(v)1.7 sodium channel. Using transient transfection of PC12 cells we found a significant reduction in membrane localization of the mutant protein compared to the wild type. Furthermore, voltage clamp experiments of mutant-transfected HEK293 cells show a complete loss of function of the sodium channel, consistent with the absence of pain phenotype. In summary, this study has identified critical amino acids needed for the normal subcellular localization and function of Na(v)1.7.
| S-EPMC2966863 | biostudies-literature
Project description:Congenital insensitivity to pain (CIP) (OMIM 243000) is a rare autosomal-recessive disorder. Clinically, CIP is characterized by insensitivity to all modalities of pain except neuropathic pain, and recurrent injuries frequently go unnoticed. CIP is caused by mutations in the SCN9A gene encoding for the Na1.7 channel.We analyzed the DNA from members of a consanguineous Pakistani family for mutations in the SCN9A gene through direct sequencing after performing linkage studies.We identified a novel missense mutation designated R523X in all affected individuals. A screening assay ruled out the possibility of polymorphism.We identified a novel mutation in the Na1.7 channel leading to CIP, extending the spectrum of mutations in the Na1.7 channel, and enhancing our understanding of the physiology of pain.
| S-EPMC2969160 | biostudies-literature
Project description:Congenital insensitivity to pain (CIP) and hereditary sensory and autonomic neuropathies (HSAN) are clinically and genetically heterogeneous disorders exclusively or predominantly affecting the sensory and autonomic neurons. Due to the rarity of the diseases and findings based mainly on single case reports or small case series, knowledge about these disorders is limited. Here, we describe the molecular workup of a large international cohort of CIP/HSAN patients including patients from normally under-represented countries. We identify 80 previously unreported pathogenic or likely pathogenic variants in a total of 73 families in the >20 known CIP/HSAN-associated genes. The data expand the spectrum of disease-relevant alterations in CIP/HSAN, including novel variants in previously rarely recognized entities such as ATL3-, FLVCR1- and NGF-associated neuropathies and previously under-recognized mutation types such as larger deletions. In silico predictions, heterologous expression studies, segregation analyses and metabolic tests helped to overcome limitations of current variant classification schemes that often fail to categorize a variant as disease-related or benign. The study sheds light on the genetic causes and disease-relevant changes within individual genes in CIP/HSAN. This is becoming increasingly important with emerging clinical trials investigating subtype or gene-specific treatment strategies.
| S-EPMC10689924 | biostudies-literature
Project description:BackgroundCongenital insensitivity to pain with anhidrosis (CIPA) (OMIM 256800) is a rare autosomal-recessive condition, also known as hereditary sensory and autonomic neuropathy type IV (HSAN-IV). The most commonly reported features include anhidrosis, intellectual disability, self-mutilation, febrile episodes, impaired temperature perception, recurrent infections and/or autonomic nervous system impairment. Major joint destruction and joint deformity known as Charcot (neuropathic) joints are also seen in CIPA patients attributed to insensitivity to joint pain.MethodsWe present a case of a 46-year-old female affected with CIPA with a known NTRK1 variant and previously unidentified variant. Minigene reporter constructs were generated encompassing the exon 8 to exon 13 of the NTRK1 gene using the reference sequence and one harboring c.1483 + 5G > A variant identified in our proband. Minigene constructs were transfected into HEK293T cells, and the transcript was analysed for splicing to evaluate the effect of this variant in splicing.ResultsThe patient (46-year-old female) exhibited right ankle joint deformity around 5 years of age. Patient also experienced lumbar compression and knee damage in adulthood. She had undergone a significant number of evaluations without clear diagnosis. Her presentation lacked many of the common clinical presentations of CIPA, and therefore, the focus of her evaluation was directed towards her unexplained joint deformities. Exome sequencing revealed a known pathogenic variant in NTRK1 (c.851 - 33T > A:p.? [Intron 7]) and a novel NTRK1 variant (c.1483 + 5G > A:p.? [Intron 11]), which was later re-classified as likely pathogenic. The patient was started on a biologic disease-modifying anti-rheumatic medication (bDMARD) due to a possible inflammatory etiology of her joint deformity. Molecular diagnosis allowed for modification of her treatment and surveillance strategies. Our minigene splicing assay demonstrated that the presence of the c.1483 + 5G > A variant has a negative effect on splicing, supporting the pathogenicity of this novel variant.
| S-EPMC11513606 | biostudies-literature