Charcot-Marie-tooth disease type 1A Association with a spontaneous point mutation in thePMP22 gene

Roa, Benjamin B.; García, Carlos; Suter, Uelli; Kulpa, Deanna A.; Wise, Carol A.; Müller, Jane; Welcher, Andrew A.; Snipes, G. Jackson; Shooter, Eric M.; Patel, Pragna I.; Lupski, James R.

doi:10.1007/bf00866335

Cited by 9 publications

(10 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In this disease the most frequently observed genetic abnormality is a duplication of a 1.5-Mb-long DNA fragment [9,14] on chromosome 17p11.2-12 [7] (CMT1A) which encompasses the gene for the peripheral myelin protein 22 (PMP22) [20]. In addition to the CMT1A duplication, point mutations in PMP22 [16] (CMT1A), mutations in the myelin protein zero (MPZ) [6] (CMT1B), and in the gap junction protein connexin 32 (Cx32) [2] (CMTX) and in the early-growth response 2 (ERG2) [22] genes can cause CMT1 [9]. In about 84 % of HNPP individuals the disorder is caused by a deletion of the same fragment which is duplicated in CMT1A [3,9].…”

Section: Methodsmentioning

confidence: 99%

PMP22 Thr118Met is not a clinically relevant CMT1 marker

Young¹,

Stögbauer

Eller

et al. 2000

Journal of Neurology

View full text Add to dashboard Cite

It is controversial if peripheral myelin protein 22 gene (PMP22) Thr118Met represents a functionally irrelevant polymorphism or, since hemizygosity for this variant has been found in two patients with Charcot-Marie-Tooth disease type 1 (CMT1 patients), it can act as a recessive CMT1 mutation. To shed further light on this variant and its diagnostic value we searched for carriers in 1018 individuals from the German general population, in 104 probands with hereditary neuropathy with liability to pressure palsies (HNPP) who were carriers of the 1.5-Mb deletion frequently associated with this disorder, in 187 patients with the 1.5-Mb duplication, and in 22 patients with a CMT1 phenotype who did not have any detectable anomaly in the PMP22 gene. Using allele-specific PCR we identified 14 [allele frequency (AF)=0.007] in the German general population, one (AF=0.01) in the HNPP group and six (AF=0.016) and two (AF=0.05) carriers of the PMP22 Thr118Met mutation in the CMT1 groups with and without gene defect. Carriers from all groups showed nerve conduction velocities which did not differ from typical values for these groups. We conclude that the hemizygous occurrence of the 118Met allele does not usually cause CMT1. Because of previous reports on its association with disease, and because its allele product shows abnormalities in in vitro expression systems, it seems possible that this mutation, together with yet unidentified factors, predisposes to CMT1. Alternatively, previously reported disease associations occurred by chance, and the 118Met allele causes biochemical abnormalities irrelevant for CMT1 formation. In either case this mutation is not a clinically relevant disease marker.

show abstract

Section: Methodsmentioning

confidence: 99%

PMP22 Thr118Met is not a clinically relevant CMT1 marker

Young¹,

Stögbauer

Eller

et al. 2000

Journal of Neurology

View full text Add to dashboard Cite

show abstract

“…In this setting, we recently found a heterozygous de novo Ser72Leu substitution in a 14‐year‐old girl with the DSD phenotype, in whom a diagnosis of CH was made on clinical ground along with a nerve biopsy performed in the first month of life 76. In codon 79, two different substitutions, namely Ser79Pro and Ser79Cys, lead to the DSD and CMT1 phenotypes, respectively 13, 81. Also, a de novo heterozygous duplication of the 17p11.2 segment has been reported in DSD patients 61, 62, 87.…”

Section: Clinical Aspects Of Dejerine–sottas Diseasementioning

confidence: 99%

Dejerine–Sottas disease and hereditary demyelinating polyneuropathy of infancy

Planté‐Bordeneuve

Saïd

2002

Muscle and Nerve

View full text Add to dashboard Cite

Dejerine-Sottas disease (DSD) was originally described as a hypertrophic polyneuropathy characterized by onset in infancy or early childhood in patients born to unaffected parents. The clinical features included distal sensory changes with ataxia; pes cavus, at times with kyphoscoliosis; motor deficit and atrophy predominating in the distal lower limbs and progressing toward the proximal limbs following a length-dependent pattern; palpable nerve hypertrophy; and Argyll-Robertson pupils. The morphological hallmark was the extensive nerve and root hypertrophy associated with demyelination-remyelination of surviving, originally myelinated axons and profuse Schwann-cell proliferation forming onion bulbs. Wide variations in clinical manifestations of chronic demyelinating polyneuropathies of early onset in children born to unaffected parents have now been reported, with only some of the characteristics required in the original study, and at least seven genes encoding the myelin proteins P0, PMP22, the transcriptional factor EGR2, and others have been implicated. Thus, DSD is now a component of the hereditary demyelinating polyneuropathies of infancy that also include subsets of the recently individualized CMT4 neuropathies. The presumed recessive transmission of patients with DSD should be confirmed by molecular genetic analysis, which is still negative in a significant proportion of patients. The nerve biopsy can be useful in patients in whom genealogical or DNA abnormalities in favor of a genetic disorder are missing, because in a few patients with a progressive or relapsing course the diagnosis of early-onset chronic inflammatory demyelinating polyneuropathy must be considered.

show abstract

“…In non informative patients, a PCR analysis of the CMT1A-REP specific junction frag-ments was performed.We used 2 sets of primers specific for the proximal and the distal REP sequences, flanking the 1.7 Kb recombination hot spot area [11]. P 0 , PMP 22 and Egr2 genes sequencing: mutation screening of the PMP 22 and P 0 genes was conducted after PCR amplification of the entire coding regions as described [12,24]. The 2 exons of the Egr2 gene were amplified with 7 overlapping sets of primers out of the nine previously reported [28,33].…”

Section: Molecular Genetic Studymentioning

confidence: 99%

The range of chronic demyelinating neuropathy of infancy: a clinico-pathological and genetic study of 15 unrelated cases

Planté‐Bordeneuve¹,

Parman

Guiochon‐Mantel

et al. 2001

Journal of Neurology

View full text Add to dashboard Cite

The concept of Dejerine-Sottas disease, which corresponds to presumed recessive demyelinating neuropathies with onset in infancy, remains controversial. To learn more on the subject, we performed a clinico-pathological and molecular genetic study in 15 unrelated patients with the Dejerine-Sottas phenotype seen over a 16 year period. There were 12 females and 3 males, born to asymptomatic parents. Study of the PMP22, P0 and Egr2 genes was performed in all cases and 14 underwent a nerve biopsy. First manifestations of neuropathy occurred before 3 years of age in all patients. An inherited disorder was suspected in 10 patients, because of their family history and/or disclosure of a molecular genetic defect in 4 of them. One patient had a recessively transmitted homozygous point mutation (Arg157Trp) of the PMP22 gene. A heterozygous duplication of the 17p11.2-12 segment was detected in one offspring of a consanguineous marriage. One patient carried a "de novo" heterozygous Ser72Leu substitution in the PMP22. A heterozygous double mutation of the P0 gene including a "de novo" Val42 deletion and an Ala221Thr substitution, maternally inherited, were found in an apparently sporadic case. No mutation of the Egr2 gene was identified. A neuropathy with focally folded myelin sheaths (CMT4B) was diagnosed in the nerve biopsy specimens of two patients. In five patients, the clinico-pathological findings along with the absence of an identified mutation suggested the diagnosis of chronic inflammatory demyelinating polyneuropathy of infantile onset. Our findings illustrate the genetic heterogeneity of cases with identified mutations, the scarcity of cases with "demonstrated" recessive transmission and the likelihood of early acquired chronic inflammatory demyelinating polyneuropathy in several patients.

show abstract

Charcot-Marie-tooth disease type 1A Association with a spontaneous point mutation in thePMP22 gene

Cited by 9 publications

References 0 publications

PMP22 Thr118Met is not a clinically relevant CMT1 marker

PMP22 Thr118Met is not a clinically relevant CMT1 marker

Dejerine–Sottas disease and hereditary demyelinating polyneuropathy of infancy

The range of chronic demyelinating neuropathy of infancy: a clinico-pathological and genetic study of 15 unrelated cases

Contact Info

Product

Resources

About