Charcot -- Marie -- Tooth neuropathy type 1A with both duplication and non-duplication

We studied a family with nine of twenty members affected withCharcot — Marie — Tooth disease type 1A (CMT1A).The proband and her four affected sibs showed no duplicationof the 17p11.2–p12 (CMT region). Two of the proband'saffected daughters and three affected grandchildren showed duplicationof the PMP-22 gene and of the marker VAW409R3 but not of themarkers VAW412R3 and EW401. Pulsed field gel electrophoresis(PFGE) revealed a 220 kb SacII fragment in one CMT1A patientwith duplication instead of a 500 kb SacII fragment as previouslyreported (1, 3, 4, 6–9). Our findings suggest a smallersize of the duplication in this CMT1A family. The disease segregateswith the same haplotype in both duplicated and nonduplicatedCMT1A patients. The clinical phenotype showed more severe weaknesswith earlier onset and motor nerve conduction velocities werecharacterized by more significant slowing in the patients withduplication than in the patients who did not show duplication.     

Point mutations of the connexin32 (GJB1) gene in X-linked dominant Charcot -- Marie -- Tooth neuropathy

Ten families with X-linked dominant CMT neuropathy (CMTX1) werescreened for point mutations of the connexin32 (Cx32, GJB1)gene. Two families showed missense mutations, respectively anA     

Origin of the de novo duplication in Charcot -- Marie -- Tooth disease type 1A: unequal nonsister chromatid exchange during spermatogenesis

A 1.5 Mb duplication within 17p11.2 is the major mutation causingboth autosomal dominant and sporadic Charcot - Marie - Toothdisease type 1A (CMT1A). An Independent origin for the mutationIn each family has been postulated. The proposed genetic mechanismcausing the CMT1A duplication is unequal nonsister chromatldexchange at melosis (unequal crossing-over). We studied theparental origin of the duplication In nine genetically sporadicCMT1A patients and demonstrated that in all cases the mutationwas the product of an unequal nonsister chromatld exchange duringspermatogenesis. The fact that only paternal de novo duplicationswere observed In the sporadic CMT1A patients suggests that malespecific factors may be operating during spermatogenesis thateither help forming the duplication and/or stabilize the duplicatedchromosome.     

Charcot-Marie-Tooth type 1B neuropathy: third mutation of serine 63 codon in the major peripheral myelin glycoprotein P0 gene

We report studies on two patients (a mother and her daughter) presenting with a Charcot-Marie-Tooth type 1 (CMT1) phenotype: low nerve conduction velocities of 13–15 m/s and an early onset at the age of walking. DNA analysis of the gene coding for the major peripheral myelin protein P0 showed a new point mutation in exon 2, which resulted in substitution of a phenylalanine for serine at amino acid position 63 of P0. This is the third mutation reported at this codon, the two previously described leading to CMT1B (serine 63 deletion), or to Dejerine-Sottas disease (cysteine for serine 63 substitution), suggesting that different phenotypes can result from alteration of a single amino acid, depending on the type of the change involved.     

A Novel Mutation in FGD4/FRABIN Causes Charcot Marie Tooth Disease Type 4H in Patients from a Consanguineous Tunisian Family

Charcot‐Marie‐Tooth (CMT) disease constitutes a clinically and genetically heterogeneous group of hereditary neuropathies characterized by progressive muscular and sensory loss in the distal extremities with chronic distal weakness, deformation of the feet, and loss of deep tendon reflexes. CMT4H is an autosomal recessive demyelinating subtype of CMT, due to mutations in FGD4/FRABIN, for which nine mutations are described to date. In this study, we describe three patients from a consanguineous Tunisian family, presenting with severe, early onset, slowly progressive, autosomal recessive demyelinating CMT, complicated by mild to severe kyphoscoliosis, consistent with CMT4H. In these patients, we report the identification of a novel homozygous frameshift mutation in FGD4: c.514_515insG; p.Ala172Glyfs*27. Our study reports the first mutation identified in FGD4 in Tunisian patients affected with CMT. It further confirms the important clinical heterogeneity observed in patients with mutations in FGD4 and the lack of phenotype/genotype correlations in CMT4H. Our results suggest that FGD4 should be screened in other early‐onset CMT subtypes, regardless of the severity of the phenotype, and particularly in patients of consanguineous descent. In Tunisians, as in other populations with high consanguinity rates, screening of genes responsible for rare autosomal recessive CMT subtypes should be prioritized.     

Electrophysiological study (EEG, VEPs, BAEPs) in patients with Charcot Marie Tooth (type HMSN I) disease

A laboratory investigation consisting of EEG recordings, BAEPs and VEPs evaluation as well as estimation of the facial nerve distal latency was performed in 9 patients who had Charcot Marie Tooth (type HMSN I) disease. 3 patients showed VEP's abnormalities (2 of them had prolonged P100 latency and one had an abnormal interocular latency difference). Another patient showed an upper normal limit value in the interocular latency difference. Abnormal BAEPs were found in 8 patients (one had I-III/IPLD prolonged, 2 of them had the latency of wave I prolonged and the remaining 6 had no readable or repeatable responses unilaterely or bilaterally). 7 out of 9 patients had the facial nerve distal latency prolonged, without any evident clinical facial weakness. Abnormal EEG recordings were found in 2 of all tested patients. Our results provide some evidence that in Charcot Marie Tooth disease the involvement of the II, VII and VIII nerves is more frequent than clinically expected and is probably related to a demyelinated process.     

Mutations in the myelin protein zero gene associated with Charcot-Marie-Tooth disease type 1B

Charcot-Marie-Tooth type 1 (CMT1) disease is an autosomal dominant neuropathy of the peripheral nerve. The majority of CMT 1 cases are due to a duplication of an 1.5-Mb DNA fragment on chromosome 17pl1.2 (CMT la). Micromutations were found in the gene for peripheral myelin protein 22 (PMp22) located in the duplicated region of CMT la, and in the peripheral myelin protein zero (PO) located on chromosome lq21-23 (CMT Ib). We have characterized two new mutations in the PO gene in two french families presenting CMT disease. Both mutations occur in the extracellular domain of the PO protein. One mutation is a de novo mutation and is from paternal origin. © 1995 Wiley-Liss, Inc.     

Mutations in the connexin 32 gene in X-linked dominant Charcot- Marie - Tooth disease (CMTX1)

X-linked dominant Charcot-Marie-Tooth disease (CMTX1) is a peripheralneuropathy which maps to Xq13 and is flanked by the locl DXS106 (Xq11.2-q12) and DXS559 (Xq13.1). Contained within thisinterval of approximately 2–3Mb of DNA is the gene, connexin32 (locus designation GJß1). This gene encodes a gapjunction protein which is expressed in large quantites withinthe liver and throughout a range of other mammmalian tissues.We have sequenced the coding region of exon 2 of this gene fromaffected Individuals in nine families with CMTX 1 and have foundmutations which segregate with the disease in eight of thesefamilies. The mutations detected include mlssense point mutationsat codons 15, 60, 63, 208, and 215, a nonsense point mutationat codon 220, deletions of one base in codon 72/3 producinga stop codon 12 codons down stream and a three base pair deletionwhich can be predicted to result in the loss of a single aminoacid. These findings are consistent with the disease CMTX1 beingthe result of mutations affecting the gene connexin 32 (Cx32).     

Mutation of the SBF2 gene, encoding a novel member of the myotubularin family, in Charcot-Marie-Tooth neuropathy type 4B2/11p15

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Mutation of the SBF2 gene,encoding a novel member of the myotubularin family,in Charcot-Marie-Tooth neuropathy type 4B2/11p15

Autosomal recessive hereditary motor and sensory neuropathy or Charcot-Marie-Tooth disease (CMT) is a severe childhood-onset neuromuscular disorder. Autosomal recessive CMT is genetically heterogeneous with one locus mapped to chromosome 11p15 (CMT4B2). The histopathological hallmarks of CMT4B2 are focal outfoldings of myelin in nerve biopsies. Homozygosity mapping, in a Turkish inbred family with four children affected by CMT characterized by focally folded myelin, provided linkage to the CMT4B2 locus. We identified a large, novel gene, named SET binding factor 2 (SBF2), that lies within this interval and is expressed in various tissues, including spinal cord and peripheral nerve. SBF2 is a member of the pseudo-phosphatase branch of myotubularins and was an obvious candidate for CMT4B2 by virtue of its striking homology to myotubularin-related protein 2 (MTMR2), causing another form of autosomal recessive CMT with outfoldings of the myelin sheaths. Molecular study of the SBF2 gene in the CMT4B family demonstrated the presence of a homozygous inframe deletion of SBF2 exons 11 and 12 in all four affected individuals. On the protein level, this mutation is predicted to disrupt an N-terminal domain that is conserved in SBF2 and its orthologues across species. Myotubularin-related proteins have been suggested to work in phosphoinositide-mediated signalling events that may also convey control of myelination. Localization of SBF2 within the candidate interval, cosegregation with the disease, expression in the peripheral nervous system, and resemblance of the histopathological phenotype to that related to mutations in its paralogue MTMR2 indicate that this gene is the CMT4B2 gene.     

Mutation analysis of the nerve specific promoter of the peripheral myelin protein 22 gene in CMT1 disease and HNPP.

We analysed the nerve specific promoter of the peripheral myelin protein 22 gene (PMP22) in a set of 15 unrelated patients with Charcot-Marie-Tooth type 1 disease (CMT1) and 16 unrelated patients with hereditary neuropathy with liability to pressure palsies (HNPP). In these patients no duplication/deletion nor a mutation in the coding region of the CMT1/ HNPP genes was detected. In one autosomal dominant CMT1 patient, we identified a base change in the non-coding exon 1A of PMP22 which, however, did not cosegregate with the disease in the family. This study indicates that mutations in the nerve specific PMP22 promoter and 5' untranslated exon will not be a common genetic cause of CMT1A and HNPP.     

Pelizaeus -- Merzbacher disease: a frameshift deletion/insertion event in the myelin proteolipid gene

Among the central nervous system (CNS) dysmyelinating disorders,Pelizaeus-Merzbacher disease (PMD) has been individualized byits X-linked mode of inheritance and the existence of correspondinganimal models. Mutations in the major myelin proteolipid (PLP)gene coding for PLP and its splicing variant DM20 protein, havebeen demonstrated in animal mutants and more recently in PMDaffected patients. We have identified, in a two-generation PMDaffected family, an insertion/deletion event in the exon IVof the PLP gene, leading to the synthesis of predicted truncatedPLP and DM20 proteins with altered carboxyl terminal end. Thisis the first report of a frameshift mutation in the PLP genein PMD.     

Mutation spectra of the ITGB2 gene in Iranian families with leukocyte adhesion deficiency type 1

Leukocyte adhesion deficiency type 1 (LAD1) is an autosomal recessive disorder clinically characterized by severe, recurrent bacterial infections, impaired pus formation and wound healing. It is caused by mutation in the ITGB2 gene, encoding the β₂ integrin subunit of the leukocyte adhesion cell molecule. This study aimed to identify disease causing mutations in 19 consanguineous families diagnosed with LAD1.Blood samples were collected after informed and written consent was obtained. Genomic DNA was extracted from peripheral blood of patients and their parents. PCR amplification of the ITGB2 gene was done using specific primers followed by sequencing for mutation detection.A total number of 14 alterations scattered throughout the ITGB2 gene were ascertained in which 10 mutations were previously reported, including c.329−6C>A, c.382G>T, c.715G>A, c.843delC, c.897+1G>A, c.1062A>T, c.1143delC, c.1877+2T>C, c.1907delA and c.2147G>C. Four novel likely pathogenic mutations consisting of c.576dupC (Asn193GlnfsX72), c.706G>A (Gly236Arg), c.897+1G>T and c.1030G>T (Glu344¹), were identified. The majority of these mutations were located in exon six, suggesting this exon as a hotspot region probably.This study emphasis on allelic heterogeneity of the ITGB2 gene in Iranian patients diagnosed with LAD1. Our results suggest that every population should develop a mutation database for rare genetic disorders to take advantage in genetic counseling clinic as well as genetic testing for rapid diagnostic purposes.     

Mutation analysis of the MEN1 gene in Belgian patients with multiple endocrine neoplasia type 1 and related diseases

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder characterized by tumors in parathyroids, enteropancreatic endocrine tissues, anterior pituitary, and other tissues. The gene for MEN1 has recently been cloned and shown to code for a 610‐amino acid protein of enigmatic function which probably acts as a tumor suppressor. Several mutations causing the MEN1 phenotype have been recently identified. In order to determine the spectrum of MEN1 gene mutations in a sample of 25 Belgian patients, we have systematically screened the 10 exons and adjacent sequences of the MEN1 gene by means of an automatic sequencing protocol. Twelve different mutations were identified including nonsense, frameshift, splicing, and missense mutations. Two of these mutations (D172Y and 357del4) occurred more than once. A missense mutation was also found in a kindred with familial hyperparathyroidism. We observed no significant correlation between the nature or position of mutation and the clinical status. We have also detected 6 intragenic polymorphisms and DNA sequence variants and have analyzed their frequencies in our population. Hum Mutat 13:54–60, 1999. © 1999 Wiley‐Liss, Inc.     

Mutation of the angiopoietin-1 gene (ANGPT1) associates with a new type of hereditary angioedema

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A Novel Mutation (D305V) in the early growth response 2 gene is associated with severe Charcot‐Marie‐Tooth type 1 disease

Hereditary motor and sensory neuropathies (HMSN) comprises a wide clinical spectrum of related disorders with defects in peripheral nerve myelination. Charcot‐Marie‐Tooth type 1 (CMT1) is the most common form and is usually a mild disease with onset in the first or second decade; however there is a interfamilial and intrafamilial clinical variation, ranging from asymptomatic expression to severe muscular weakness and atrophy. Recently point mutations in the early growth response 2 gene (EGR2/Krox‐20) have been associated with hereditary myelinopathies. We investigated for mutations at the EGR2 gene a patient with severe CMT1 phenotype. Direct sequencing of EGR2 gene showed a heterozygous A T transversion at nucleotide 1064 that predicts an Asp305Val substitution within the first zinc‐finger domain. The finding of a novel EGR2 mutation associated with a different phenotype confirms that peripheral neuropathies represent a continuum spectrum of related disorders due to an underlying defect in myelination. Hum Mutat 14:353–354, 1999. © 1999 Wiley‐Liss, Inc.