Genes for hereditary sensory and autonomic neuropathies: a genotype-phenotype correlation.
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.
Rotthier
Annelies
A
Peripheral Neuropathy Group, VIB-Department of Molecular Genetics, University of Antwerp, Universiteitsplein 1, Antwerpen, Belgium.
Baets
Jonathan
J
De Vriendt
Els
E
Jacobs
An
A
Auer-Grumbach
Michaela
M
Lévy
Nicolas
N
Bonello-Palot
Nathalie
N
Kilic
Sara Sebnem
SS
Weis
Joachim
J
Nascimento
Andrés
A
Swinkels
Marielle
M
Kruyt
Moyo C
MC
Jordanova
Albena
A
De Jonghe
Peter
P
Timmerman
Vincent
V
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
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