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Clinical and Molecular Characterization of PMP22 point mutations in Taiwanese patients with Inherited Neuropathy.

ABSTRACT: Point mutations in the peripheral myelin protein 22 (PMP22) gene have been identified to cause demyelinating Charcot-Marie-Tooth disease (CMT) and hereditary neuropathy with liability to pressure palsy (HNPP). To investigate the mutation spectrum of PMP22 in Han-Chinese population residing in Taiwan, 53 patients with molecularly unassigned demyelinating CMT and 52 patients with HNPP-like neuropathy of unknown genetic causes were screened for PMP22 mutations by Sanger sequencing. Three point mutations were identified in four patients with demyelinating CMT, including c.256?C?>?T (p.Q86X) in two, and c.310delA (p.I104FfsX7) and c.319?+?1G?>?A in one each. One PMP22 missense mutation, c.124?T?>?C (p.C42R), was identified in a patient with HNPP-like neuropathy. The clinical presentations of these mutations vary from mild HNPP-like syndrome to severe infantile-onset demyelinating CMT. In vitro analyses revealed that both PMP22 p.Q86X and p.I104FfsX7 mutations result in truncated PMP22 proteins that are almost totally retained within cytosol, whereas the p.C42R mutation partially impairs cell membrane localization of PMP22 protein. In conclusion, PMP22 point mutations account for 7.5% and 1.9% of demyelinating CMT and HNPP patients with unknown genetic causes, respectively. This study delineates the clinical and molecular features of PMP22 point mutations in Taiwan, and emphasizes their roles in demyelinating CMT or HNPP-like neuropathy.

SUBMITTER: Liao YC

PROVIDER: S-EPMC5681590 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Clinical and Molecular Characterization of PMP22 point mutations in Taiwanese patients with Inherited Neuropathy.

Liao Yi-Chu YC Tsai Pei-Chien PC Lin Thy-Sheng TS Hsiao Cheng-Tsung CT Chao Nai-Chen NC Lin Kon-Ping KP Lee Yi-Chung YC

Scientific reports 20171110 1

Point mutations in the peripheral myelin protein 22 (PMP22) gene have been identified to cause demyelinating Charcot-Marie-Tooth disease (CMT) and hereditary neuropathy with liability to pressure palsy (HNPP). To investigate the mutation spectrum of PMP22 in Han-Chinese population residing in Taiwan, 53 patients with molecularly unassigned demyelinating CMT and 52 patients with HNPP-like neuropathy of unknown genetic causes were screened for PMP22 mutations by Sanger sequencing. Three point muta ...[more]

PMID: 29127354

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Project description:BACKGROUND:Haploinsufficiency of PMP22 causes hereditary neuropathy with liability to pressure palsies. However, the biological functions of the PMP22 protein in humans have largely been unexplored owing to the absence of patients with PMP22-null mutations. OBJECTIVE:To investigate the function of PMP22 in the peripheral nervous system by studying a boy without the PMP22 gene and mice without the Pmp22 gene. DESIGN:The clinical and pathological features of a patient with a PMP22 homozygous deletion are compared with those of Pmp22-null mice. SETTING:Clinical evaluation was performed at tertiary hospitals in the United Kingdom. Molecular diagnosis was performed at the West Midlands Regional Genetics Laboratory. Immunohistochemistry and electron microscopy analyses were conducted at Wayne State University, Detroit, Michigan. Analysis of the Pmp22 +/- and null mice was performed at Vanderbilt University, Nashville, Tennessee. PARTICIPANT:A 7-year-old boy without the PMP22 gene. RESULTS:Motor and sensory deficits in the proband were nonlength-dependent. Weakness was found in cranial muscles but not in the limbs. Large fiber sensory modalities were profoundly abnormal, which started prior to the maturation of myelin. This is in line with the temporal pattern of PMP22 expression predominantly in cranial motor neurons and dorsal root ganglia during embryonic development, becoming undetectable in adulthood. Moreover, there were conspicuous maturation defects of myelinating Schwann cells; these defects were more significant in motor nerve fibers than in sensory nerve fibers. CONCLUSIONS:Taken together, the data suggest that PMP22 is important for the normal function of neurons that express PMP22 during early development, such as cranial motor neurons and spinal sensory neurons. Moreover, PMP22 deficiency differentially affects myelination between motor and sensory nerves, which may have contributed to the unique clinical phenotype in the patient with an absence of PMP22.

Project description:Background: X-linked agammaglobulinemia (XLA) is caused by a mutation of the Bruton's tyrosine kinase (BTK) gene and is the most common genetic mutation in patients with congenital agammaglobulinemia. The aim of this study was to analyze the clinical features, genetic defects, and/or BTK expression in patients suspected of having XLA who were referred from the Taiwan Foundation of Rare Disorders (TFRD). Methods: Patients with recurrent bacterial infections in the first 2 years of life, serum IgG/A/M below 2 standard deviations of the normal range, and ?2% CD19+B cells were enrolled during the period of 2004-2019. The frequency of infections, pathogens, B-lymphocyte subsets, and family pedigree were recorded. Peripheral blood samples were sent to our institute for BTK expression and genetic analysis. Results: Nineteen (from 16 families) out of 29 patients had BTK mutations, including 7 missense mutations, 7 splicing mutations, 1 nonsense mutation, 2 huge deletions, and 2 nucleotide deletions. Six novel mutations were detected: c.504G>T [p.K168N], c.895-2A>G [p.Del K290 fs 23*], c.910T>G [p.F304V], c.1132T>C [p.T334H], c.1562A>T [p.D521V], and c.1957delG [Del p.D653 fs plus 45 a.a.]. All patients with BTK mutations had obviously decreased BTK expressions. Pseudomonas sepsis developed in 14 patients and led to both Shanghai fever and recurrent hemophagocytic lymphohistiocytosis (HLH). Recurrent sinopulmonary infections and bronchiectasis occurred in 11 patients. One patient died of pseudomonas sepsis and another died of hepatocellular carcinoma before receiving optimal treatment. Two patients with contiguous gene deletion syndrome (CGS) encompassing the TIMM8A/DDP1 gene presented with early-onset progressive post-lingual sensorineural Deafness, gradual Dystonia, and Optic Neuronopathy syndrome (DDON) or Mohr-Tranebjaerg syndrome (MTS). Conclusion: Pseudomonas sepsis was more common (74%) than recurrent sinopulmonary infections in Taiwanese XLA patients, and related to Shanghai fever and recurrent HLH, both of which were prevented by regular immunoglobulin infusions. Approximately 10% of patients belonged to CGS involving the TIMM8A/DDP1 gene and presented with the DDON/MTS phenotype in need of aggressive psychomotor therapy.

Dataset Information

Clinical and Molecular Characterization of PMP22 point mutations in Taiwanese patients with Inherited Neuropathy.

Publications

Clinical and Molecular Characterization of PMP22 point mutations in Taiwanese patients with Inherited Neuropathy.

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