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1.
Yasuhiro Indo 《Human mutation》2001,18(6):462-471
Congenital insensitivity to pain with anhidrosis (CIPA), also referred to as hereditary sensory and autonomic neuropathy type IV (HSAN‐IV), is an autosomal recessive hereditary disorder characterized by recurrent episodic fever, anhidrosis (inability to sweat), absence of reaction to noxious stimuli, self‐mutilating behavior, and mental retardation. The TRKA (NTRK1) gene located on chromosome 1 (1q21‐q22), consists of 17 exons and spans at least 23 kb. TRKA encodes the receptor tyrosine kinase (RTK) for nerve growth factor (NGF) and is the gene responsible for CIPA. Defects in NGF signal transduction at the TRKA receptor lead to failure to support survival of sympathetic ganglion neurons and nociceptive sensory neurons derived from the neural crest. Thirty‐seven different TRKA mutations, identified in patients in various countries, including nine frameshift, seven nonsense, seven splice, and 14 missense mutations, are distributed in an extracellular domain involved in NGF binding, as well as in the intracellular signal‐transduction domain. Extensive analysis of CIPA mutations and associated intragenic polymorphisms should facilitate detection of CIPA mutations and aid in the diagnosis and genetic counseling of this painless but severe genetic disorder with devastating complications. In addition, naturally occurring TRKA missense mutations with loss of function provide considerable insight into the structure–function relationship in the RTK family. Further, molecular pathology of CIPA would provide unique opportunities to explore critical roles of the autonomic sympathetic nervous system as well as peripheral sensory nervous system that transmit noxious stimuli in humans. Hum Mutat 18:462–471, 2001. © 2001 Wiley‐Liss, Inc. 相似文献
2.
Gongshe Han Sita D. Gupta Kenneth Gable Somashekarappa Niranjanakumari Prasun Moitra Florian Eichler Robert H. Brown Jr. Jeffrey M. Harmon Teresa M. Dunn 《Proceedings of the National Academy of Sciences of the United States of America》2009,106(20):8186-8191
Serine palmitoyltransferase (SPT) catalyzes the first committed step in sphingolipid biosynthesis. In yeast, SPT is composed of a heterodimer of 2 highly-related subunits, Lcb1p and Lcb2p, and a third subunit, Tsc3p, which increases enzyme activity markedly and is required for growth at elevated temperatures. Higher eukaryotic orthologs of Lcb1p and Lcb2p have been identified, but SPT activity is not highly correlated with coexpression of these subunits and no ortholog of Tsc3p has been identified. Here, we report the discovery of 2 proteins, ssSPTa and ssSPTb, which despite sharing no homology with Tsc3p, each substantially enhance the activity of mammalian SPT expressed in either yeast or mammalian cells and therefore define an evolutionarily conserved family of low molecular weight proteins that confer full enzyme activity. The 2 ssSPT isoforms share a conserved hydrophobic central domain predicted to reside in the membrane, and each interacts with both hLCB1 and hLCB2 as assessed by positive split ubiquitin 2-hybrid analysis. The presence of these small subunits, along with 2 hLCB2 isofoms, suggests that there are 4 distinct human SPT isozymes. When each SPT isozyme was expressed in either yeast or CHO LyB cells lacking endogenous SPT activity, characterization of their in vitro enzymatic activities, and long-chain base (LCB) profiling revealed differences in acyl-CoA preference that offer a potential explanation for the observed diversity of LCB seen in mammalian cells. 相似文献
3.
Minde J Toolanen G Andersson T Nennesmo I Remahl IN Svensson O Solders G 《Muscle & nerve》2004,30(6):752-760
We have studied a large Swedish family with a mutation in the nerve growth factor beta (NGFB) gene causing insensitivity to deep pain without anhidrosis (hereditary sensory and autonomic neuropathy, type V; HSAN V). Painfree joint destruction and fractures were common. Peripheral nerve conduction was normal, but temperature thresholds were increased. Sural nerve biopsies showed a moderate loss of A delta fibers and a severe reduction of C fibers. The three most severely affected cases were all born to consanguineous parents, and were homozygotes for the causal genetic mutation. Treatment of these patients is discussed. 相似文献
4.
Hongyan Bi Yunying Gao Sheng Yao Mingrui Dong Alexander Peter Headley Yun Yuan 《Neuropathology》2007,27(5):429-433
Hereditary sensory and autonomic neuropathy type I (HSAN I) is an autosomal dominant disorder of the peripheral nervous system characterized by marked progressive sensory loss, with variable autonomic and motor involvement. The HSAN I locus maps to chromosome 9q22.1–22.3 and is caused by mutations in the gene coding for serine palmitoyltransferase long chain base subunit 1 (SPTLC1). Sequencing in HSAN I families have previously identified mutations in exons 5, 6 and 13 of this gene. Here we report the clinical, electrophysiological and pathological findings of a proband in a Chinese family with HSAN I. The affected members showed almost typical clinical features. Electrophysiological findings showed an axonal, predominantly sensory, neuropathy with motor and autonomic involvement. Sural nerve biopsy showed loss of myelinated and unmyelinated fibers. SPTLC1 mutational analysis revealed the C133W mutation, a mutation common in British HSAN I families. 相似文献
5.
Ruqaiah Altassan Haya Al Saud Tariq Ahmad Masoodi Haya Al Dosssari Ola Khalifa Hamad Al‐Zaidan Nadia Sakati Zuhair Rhabeeni Zuhair Al‐Hassnan Yousef Binamer Nadia Alhashemi William Wade Zayed Al‐Zayed Moeen Al‐Sayed Mohamed A. Al‐Muhaizea Brian Meyer Mohammad Al‐Owain Salma M. Wakil 《American journal of medical genetics. Part A》2017,173(4):1009-1016
6.
Posterior column ataxia with retinitis pigmentosa coexisting with sensory‐autonomic neuropathy and leukemia due to the homozygous p.Pro221Ser FLVCR1 mutation
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7.
Beena Suresh Vaishnavi Reddy Ingo Kurth Sujatha Jagadeesh 《Neuro-ophthalmology (Aeolus Press)》2013,37(5):310-312
Hereditary Sensory and Autonomic Neuropathy IV (HSAN IV) or Congenital Insensitivity to pain and Anhidrosis is an autosomal recessive condition. It is characterized by absence of reaction to painful stimuli, anhidrosis, self-mutilating behaviour and episodic fever. We report a child with HSAN IV who presented primarily with recurrent corneal ulcers and the classical history helped us clinch the diagnosis. Molecular testing revealed a homozygous pathogenic frameshift mutation in NTRK1 c.717delG, p.(Met239fs). Molecular testing is confirmatory and this will help the family in future prenatal diagnosis. 相似文献
8.
Babar Kayani Mathew David Sewell Johnson Platinum Andre Olivier Timothy W.R. Briggs Deborah M. Eastwood 《European journal of paediatric neurology》2017,21(2):318-326
Background
Congenital indifference to pain with anhidrosis (CIPA) is a rare hereditary neuropathy, which is associated with defective sensation to noxious stimuli and autonomic dysfunction. The objective of the study was to report on the orthopaedic manifestations of this condition and provide an evidence-based approach for management.Methods
Retrospective review of 14 consecutive patients with CIPA referred to a single tertiary centre. Mean age of diagnosis was 2.5 years (range 0.5 to 11 years).Results
Patients presented with a range of orthopaedic problems including fractures, infections, growth disturbance, joint subluxation and Charcot joints affecting the limbs and spine. Conservative treatment with closed reduction and cast immobilisation was satisfactory for stress fractures of the lower extremity and Charcot joints. Posterior instrumented correction of scoliosis was associated with a high-risk of infection requiring reoperation for debridement and removal of posterior instrumentation. Growth disturbance leading to leg-length discrepancies were managed with shoe raises and corrective osteotomies. Aspiration and cultures may be used to differentiate between acute fracture and infection.Conclusions
Preventative treatment strategies with appropriately padded shoe-wear, gait and posture modification, parental education regarding environmental thermoregulation, and behavioural support are essential for improving prognosis and reducing long-term complications. 相似文献9.
Hereditary sensory and autonomic neuropathies (HSAN) are a group of clinically and genetically heterogeneous disorders that are associated with sensory dysfunction. Among these, HSAN type 2 (HSAN2; MIM 201300) is a rare recessive disease that is characterized by an early age of onset with distal and proximal sensory loss, dysfunction of the autonomic nervous system, loss of the tendon reflex, the presence of various mutilations, and the slow progression of the disease over time. The authors report a Korean patient with the clinical features of HSAN2, who was compound heterozygous for two loss-of-function mutations in the HSN2 gene: c.217C > T (Gln73X) and c.1134_1135insT (Asp379fsX1). The Gln73X mutation was a novel mutation while the Asp379fsX1 mutation has recently been reported in a Japanese patient with HSAN2. These results expanded the spectrum of mutations of the HSN2 gene by identifying a novel truncating mutation in a Korean patient and further support the hypothesis that HSN2 is a causative gene for HSAN2.Byoung Joon Kim and Chang-Seok Ki contributed equally to this work 相似文献
10.
Paola Fortugno Francesco Angelucci Gianluca Cestra Letizia Camerota Angelo Salvatore Ferraro Sonia Cordisco Luigi Uccioli Daniele Castiglia Barbara De Angelis Ingo Kurth Uwe Kornak Francesco Brancati 《Human mutation》2019,40(1):106-114
Hereditary sensory and autonomic neuropathies (HSAN) are clinically and genetically heterogeneous disorders, characterized by a progressive sensory neuropathy often complicated by ulcers and amputations, with variable motor and autonomic involvement. Several pathways have been implicated in the pathogenesis of neuronal degeneration in HSAN, while recent observations point to an emerging role of cytoskeleton organization and function. Here, we report novel biallelic mutations in the DST gene encoding dystonin, a large cytolinker protein of the plakin family, in an adult form of HSAN type VI. Affected individuals harbored the premature termination codon variant p.(Lys4330*) in trans with the p.(Ala203Glu) change affecting a highly conserved residue in an isoform‐specific N‐terminal region of dystonin. Functional studies showed defects in actin cytoskeleton organization and consequent delayed cell adhesion, spreading and migration, while recombinant p.Ala203Glu dystonin loses the ability to bind actin. Our data aid in the clinical and molecular delineation of HSAN‐VI and suggest a central role for cell‐motility and cytoskeletal defects in its pathogenesis possibly interfering with the neuronal outgrowth and guidance processes. 相似文献