Founder SH3TC2 mutations are responsible for a CMT4C French-Canadians cluster

Gosselin, Isabelle; Thiffault, Isabelle; Tétreault, Martine; Chau, Vann; Dicaire, Marie‐Josée; Loisel, Lina; Emond, Monique; Senderek, Jan; Mathieu, Jean; Dupré, Nicolas; Vanasse, Michel; Puymirat, Jack; Brais, Bernard

doi:10.1016/j.nmd.2008.04.001

Cited by 35 publications

(37 citation statements)

References 24 publications

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“…During the last two decades, genetic studies have continuously documented new CMT4C cases (4,5,7,(12)(13)(14)(15). Although the recent identification of SH3TC2 as the gene mutated in CMT4C (4) immediately led to substantially improved clinical diagnostic and genetic counseling in the affected families, the functional role of the SH3TC2 protein in peripheral nerves remained unknown.…”

Section: Discussionmentioning

confidence: 99%

“…An explanation for this difference might be the progressive aspect of the disease; the demyelination phenotype present in symptomatic patient biopsies could be the consequence of an early hypomyelination. In addition, a substantial heterogeneity in the age of onset and severity of the disease was observed among patients with CMT4C (4,5,(12)(13)(14)(15).…”

Section: Discussionmentioning

confidence: 99%

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SH3TC2/KIAA1985 protein is required for proper myelination and the integrity of the node of Ranvier in the peripheral nervous system

Arnaud¹,

Zenker

Charles³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Charcot–Marie–Tooth disease type 4C (CMT4C) is an early-onset, autosomal recessive form of demyelinating neuropathy. The clinical manifestations include progressive scoliosis, delayed age of walking, muscular atrophy, distal weakness, and reduced nerve conduction velocity. The gene mutated in CMT4C disease, SH3TC2 / KIAA1985 , was recently identified; however, the function of the protein it encodes remains unknown. We have generated knockout mice where the first exon of the Sh3tc2 gene is replaced with an enhanced GFP cassette. The Sh3tc2 Δ Ex1 /Δ Ex1 knockout animals develop progressive peripheral neuropathy manifested by decreased motor and sensory nerve conduction velocity and hypomyelination. We show that Sh3tc2 is specifically expressed in Schwann cells and localizes to the plasma membrane and to the perinuclear endocytic recycling compartment, concordant with its possible function in myelination and/or in regions of axoglial interactions. Concomitantly, transcriptional profiling performed on the endoneurial compartment of peripheral nerves isolated from control and Sh3tc2 Δ Ex1 /Δ Ex1 animals uncovered changes in transcripts encoding genes involved in myelination and cell adhesion. Finally, detailed analyses of the structures composed of compact and noncompact myelin in the peripheral nerve of Sh3tc2 Δ Ex1 /Δ Ex1 animals revealed abnormal organization of the node of Ranvier, a phenotype that we confirmed in CMT4C patient nerve biopsies. The generated Sh3tc2 knockout mice thus present a reliable model of CMT4C neuropathy that was instrumental in establishing a role for Sh3tc2 in myelination and in the integrity of the node of Ranvier, a morphological phenotype that can be used as an additional CMT4C diagnostic marker.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

SH3TC2/KIAA1985 protein is required for proper myelination and the integrity of the node of Ranvier in the peripheral nervous system

Arnaud¹,

Zenker

Charles³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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100

105

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“…This micro-regional cluster further raised the possibility of a recessive founder mutation shared by these three families. Families 1 and 3 originate from the Gaspésie region also known for its regional founder effects [16,17]. The clinical features of the seven cases are summarized in Table 1.…”

Section: Resultsmentioning

confidence: 99%

Tremor–ataxia with central hypomyelination (TACH) leukodystrophy maps to chromosome 10q22.3–10q23.31

et al. 2010

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Leukodystrophies are a heterogeneous group of disorders associated with abnormal central nervous system white matter. The clinical features invariably include upper motor neuron signs and developmental regression with or without other neurological manifestations. The objective of this study was to characterize clinically and genetically a new form of childhood-onset leukodystrophy with ataxia and tremor. We recruited seven French-Canadian cases belonging to five families affected by an unknown form of childhood-onset leukodystrophy. Genome-wide scans (GWS) were performed using the Illumina Hap310 or Hap610 Bead Chip to identify regions of shared homozygosity that were further studied for linkage with STS markers. All cases presented between the ages of 1 and 5 years with spasticity along with other upper motor neuron signs, prominent postural tremor, and cerebellar signs. Though motor regression is a constant feature, cognitive functions are relatively preserved, even late in the course of the disease. The higher frequency of founder diseases in the French-Canadian population and the segregation in pedigrees are suggestive of a recessive mode of inheritance. By homozygosity mapping, we established linkage to a 12.6-Mb SNP-haplotyped region on chromosome 10q22.3–10q23.31 (maximum LOD score: 5.47). We describe an autosomal recessive childhood-onset leukodystrophy with ataxia and tremor mapping to a 12.6 Mb interval on chromosome 10q22.3–10q23.31. Identification of the mutated gene will allow precise diagnosis and genetic counseling and shed light on how its perturbed function leads to white matter abnormalities.

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“…In the available literature, the only two exceptions are a CMT patient with median motor NCVs of 42.0 m/s, amplitude of 1.9 mV, and unexcitable median sensory nerves [12] and a patient reported by ref. [19] with median motor NCVs of 39.8 m/s, amplitude of 6.6 mV and median sensory NCVs of 43. 0 m/s, and amplitude of 2.9 mV.…”

Section: Discussionmentioning

confidence: 99%

Unraveling the genetic landscape of autosomal recessive Charcot-Marie-Tooth neuropathies using a homozygosity mapping approach

et al. 2014

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Autosomal recessive forms of Charcot-Marie-Tooth disease (ARCMT) are rare but severe disorders of the peripheral nervous system. Their molecular basis is poorly understood due to the extensive genetic and clinical heterogeneity, posing considerable challenges for patients, physicians, and researchers. We report on the genetic findings from a systematic study of a large collection of 174 independent ARCMT families. Initial sequencing of the three most common ARCMT genes (ganglioside-induced differentiation protein 1—GDAP1, SH3 domain and tetratricopeptide repeats-containing protein 2—SH3TC2, histidine-triad nucleotide binding protein 1—HINT1) identified pathogenic mutations in 41 patients. Subsequently, 87 selected nuclear families underwent single nucleotide polymorphism (SNP) genotyping and homozygosity mapping, followed by targeted screening of known ARCMT genes. This strategy provided molecular diagnosis to 22 % of the families. Altogether, our unbiased genetic approach identified pathogenic mutations in ten ARCMT genes in a total of 41.3 % patients. Apart from a newly described founder mutation in GDAP1, the majority of variants constitute private molecular defects. Since the gene testing was independent of the clinical phenotype of the patients, we identified mutations in patients with unusual or additional clinical features, extending the phenotypic spectrum of the SH3TC2 gene. Our study provides an overview of the ARCMT genetic landscape and proposes guidelines for tackling the genetic heterogeneity of this group of hereditary neuropathies.

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Founder SH3TC2 mutations are responsible for a CMT4C French-Canadians cluster

Cited by 35 publications

References 24 publications

SH3TC2/KIAA1985 protein is required for proper myelination and the integrity of the node of Ranvier in the peripheral nervous system

SH3TC2/KIAA1985 protein is required for proper myelination and the integrity of the node of Ranvier in the peripheral nervous system

Tremor–ataxia with central hypomyelination (TACH) leukodystrophy maps to chromosome 10q22.3–10q23.31

Unraveling the genetic landscape of autosomal recessive Charcot-Marie-Tooth neuropathies using a homozygosity mapping approach

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