title: Genes for hereditary sensory and autonomic neuropathies: a genotype-phenotype correlation.
abstract: Hereditary sensory and autonomic neuropathies (HSAN) are clinically and genetically heterogeneous disorders characterized by axonal atrophy and degeneration, exclusively or predominantly affecting the sensory and autonomic neurons. So far, disease-associated mutations have been identified in seven genes: two genes for autosomal dominant (SPTLC1 and RAB7) and five genes for autosomal recessive forms of HSAN (WNK1/HSN2, NTRK1, NGFB, CCT5 and IKBKAP). We performed a systematic mutation screening of the coding sequences of six of these genes on a cohort of 100 familial and isolated patients diagnosed with HSAN. In addition, we screened the functional candidate gene NGFR (p75/NTR) encoding the nerve growth factor receptor. We identified disease-causing mutations in SPTLC1, RAB7, WNK1/HSN2 and NTRK1 in 19 patients, of which three mutations have not previously been reported. The phenotypes associated with mutations in NTRK1 and WNK1/HSN2 typically consisted of congenital insensitivity to pain and anhidrosis, and early-onset ulcero-mutilating sensory neuropathy, respectively. RAB7 mutations were only found in patients with a Charcot-Marie-Tooth type 2B (CMT2B) phenotype, an axonal sensory-motor neuropathy with pronounced ulcero-mutilations. In SPTLC1, we detected a novel mutation (S331F) corresponding to a previously unknown severe and early-onset HSAN phenotype. No mutations were found in NGFB, CCT5 and NGFR. Overall disease-associated mutations were found in 19% of the studied patient group, suggesting that additional genes are associated with HSAN. Our genotype-phenotype correlation study broadens the spectrum of HSAN and provides additional insights for molecular and clinical diagnosis.
authors: Peripheral Neuropathy Group, VIB-Department of Molecular Genetics, University of Antwerp, Universiteitsplein 1, Antwerpen, Belgium.
authors: Annelies
authors: A
authors: Rotthier
authors: Jonathan
authors: J
authors: Baets
authors: Els
authors: E
authors: De Vriendt
authors: An
authors: A
authors: Jacobs
authors: Michaela
authors: M
authors: Auer-Grumbach
authors: Nicolas
authors: N
authors: Lévy
authors: Nathalie
authors: N
authors: Bonello-Palot
authors: Sara Sebnem
authors: SS
authors: Kilic
authors: Joachim
authors: J
authors: Weis
authors: Andrés
authors: A
authors: Nascimento
authors: Marielle
authors: M
authors: Swinkels
authors: Moyo C
authors: MC
authors: Kruyt
authors: Albena
authors: A
authors: Jordanova
authors: Peter
authors: P
authors: De Jonghe
authors: Vincent
authors: V
authors: Timmerman
mesh_terms: D000328:Adult; D000368:Aged; D002352:Carrier Proteins / Q000235:genetics; D056404:Chaperonin Containing TCP-1 / Q000235:genetics; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005091:Exons / Q000235:genetics; D005260:Female; D005819:Genetic Markers / Q000235:genetics*; D005838:Genotype; D009477:Hereditary Sensory and Autonomic Neuropathies / Q000235:genetics* / Q000473:pathology*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008875:Middle Aged; D015778:Minor Histocompatibility Antigens; D008967:Molecular Biology; D010334:Paternity; D010641:Phenotype; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D020800:Receptor, Nerve Growth Factor / Q000235:genetics; D020917:Receptor, trkA / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D051102:Serine C-Palmitoyltransferase / Q000235:genetics; D035602:Transcriptional Elongation Factors; D000076204:WNK Lysine-Deficient Protein Kinase 1; D020691:rab GTP-Binding Proteins / Q000235:genetics; D000090802:rab7 GTP-Binding Proteins
chemical_list: C533301:CCT5 protein, human; D002352:Carrier Proteins; C114720:Elp1 protein, human; D005819:Genetic Markers; D047908:Intracellular Signaling Peptides and Proteins; D015778:Minor Histocompatibility Antigens; D020800:Receptor, Nerve Growth Factor; D035602:Transcriptional Elongation Factors; D000090802:rab7 GTP-Binding Proteins; C000716463:rab7 GTP-binding proteins, human; C487784:SPTLC1 protein, human; D051102:Serine C-Palmitoyltransferase; D020917:Receptor, trkA; D017346:Protein Serine-Threonine Kinases; D000076204:WNK Lysine-Deficient Protein Kinase 1; C498743:WNK1 protein, human; D056404:Chaperonin Containing TCP-1; D020691:rab GTP-Binding Proteins