Dataset Information

Coexistence of a T118M PMP22 missense mutation and chromosome 17 (17p11.2-p12) deletion.

ABSTRACT: We describe a 6-year-old girl with a T118M PMP22 mutation and heterozygous deletion of PMP22 on chromosome 17 (17p11.2-p12) resulting in a severe sensorimotor polyneuropathy.This study is a case report in which the relevant mutations are described.Foot pain, cavovarus feet, tibialis anterior atrophy, absent reflexes, and inability to walk were found when the patient was age 6 years. Nerve conduction studies showed evidence of a sensorimotor polyneuropathy and compressive mononeuropathies of bilateral median nerves at the wrist and ulnar nerves at the elbow. Genetic testing revealed deletion of a PMP22 allele and T118M PMP22 mutation in the remaining allele.The severe sensorimotor polyneuropathy and hereditary neuropathy with liability to pressure palsies (HNPP) in this patient was likely a consequence of both decreased expression of PMP22 causing features consistent with HNPP and unopposed expression of the T118M mutant form of PMP22 that is relatively benign in the heterozygous state. The T118M mutant form of PMP22 can be disease-modifying in the appropriate circumstances.

SUBMITTER: Jerath NU

PROVIDER: S-EPMC4596757 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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Coexistence of a T118M PMP22 missense mutation and chromosome 17 (17p11.2-p12) deletion.

Jerath Nivedita U NU Kamholz John J Grider Tiffany T Harper Amy A Swenson Andrea A Shy Michael E ME

Muscle & nerve 20150619 5

<h4>Introduction</h4>We describe a 6-year-old girl with a T118M PMP22 mutation and heterozygous deletion of PMP22 on chromosome 17 (17p11.2-p12) resulting in a severe sensorimotor polyneuropathy.<h4>Methods</h4>This study is a case report in which the relevant mutations are described.<h4>Results</h4>Foot pain, cavovarus feet, tibialis anterior atrophy, absent reflexes, and inability to walk were found when the patient was age 6 years. Nerve conduction studies showed evidence of a sensorimotor po ...[more]

PMID: 26012543

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Project description:Smith-Magenis syndrome (SMS) is caused by an approximately 4-Mb heterozygous interstitial deletion on chromosome 17p11.2 in approximately 80%-90% of affected patients. Three large ( approximately 200 kb), complex, and highly homologous ( approximately 98%) low-copy repeats (LCRs) are located inside or flanking the SMS common deletion. These repeats, also known as "SMS-REPs," are termed "distal," "middle," and "proximal." The directly oriented distal and proximal copies act as substrates for nonallelic homologous recombination resulting in both the deletion associated with SMS and the reciprocal duplication: dup(17)(p11.2p11.2). Using restriction enzyme cis-morphism analyses and direct sequencing, we mapped the regions of strand exchange in 16 somatic-cell hybrids that harbor only the recombinant SMS-REP. Our studies showed that the sites of crossovers were distributed throughout the region of homology between the distal and proximal SMS-REPs. However, despite approximately 170 kb of high homology, 50% of the recombinant junctions occurred in a 12.0-kb region within the KER gene clusters. DNA sequencing of this hotspot (positional preference for strand exchange) in seven recombinant SMS-REPs narrowed the crossovers to an approximately 8-kb interval. Four of them occurred in a 1,655-bp region rich in polymorphic nucleotides that could potentially reflect frequent gene conversion. For further evaluation of the strand exchange frequency in patients with SMS, novel junction fragments from the recombinant SMS-REPs were identified. As predicted by the reciprocal-recombination model, junction fragments were also identified from this hotspot region in patients with dup(17)(p11.2p11.2), documenting reciprocity of the positional preference for strand exchange. Several potential cis-acting recombination-promoting sequences were identified within the hotspot. It is interesting that we found 2.1-kb AT-rich inverted repeats flanking the proximal and middle KER gene clusters but not the distal one. The role of any or all of these in stimulating double-strand breaks around this positional recombination hotspot remains to be explored.

Dataset Information

Coexistence of a T118M PMP22 missense mutation and chromosome 17 (17p11.2-p12) deletion.

Publications

Coexistence of a T118M PMP22 missense mutation and chromosome 17 (17p11.2-p12) deletion.

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