GDAP1 mutations are frequent among Brazilian patients with autosomal recessive axonal Charcot-Marie-Tooth disease

Figueiredo, Fernanda Barbosa; Silva, Wilson A.; Giuliatti, Silvana; Tomaselli, Pedro J.; Lourenço, Charles Marques; Gouvêa, Silmara de Paula; Covaleski, Anna Paula Paranhos Miranda; Hallak, Jaime E. C.; Marques, Wilson

doi:10.1016/j.nmd.2021.03.005

“…28 Figueiredo et al, in 2021, observed that the GDAP1 gene was a frequent cause of AR-CMT2 in Brazilian individuals, accounting for 7.4% of axonal CMT cases. 29 In our cohort, GDAP1 variants were responsible for 3.55% (n = 7)…”

Section: Discussionmentioning

confidence: 75%

“…In 2020, Padilha et al reported the frequencies of the MFN2 and GDAP1 variants in southern Brazil, with each accounting for 2% of cases 28 . Figueiredo et al, in 2021, observed that the GDAP1 gene was a frequent cause of AR‐CMT2 in Brazilian individuals, accounting for 7.4% of axonal CMT cases 29 …”

Section: Discussionmentioning

confidence: 99%

Charcot‐Marie‐Tooth disease: Genetic profile of patients from a large Brazilian neuromuscular reference center

Cavalcanti

¹

,

Santos

²

,

Martins

³

et al. 2021

J Peripheral Nervous Sys

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This study aimed to describe the clinical, genetic, and epidemiological features of Charcot-Marie-Tooth disease (CMT) in Brazilian patients from a tertiary center, and to compare our data with previously published findings. This retrospective observational study conducted between February 2015 and July 2020 evaluated 503 patients (94 families and 192 unrelated individuals), diagnosed with CMT. Clinical and neurophysiological data were obtained from electronic medical records and blood samples were used for genetic analyses. Multiplex ligation-dependent probe amplification was used to assess duplications/deletions in PMP22. Sanger sequencing of GJB1 was performed in cases of suspected demyelinating CMT. Targeted gene panel sequencing was used for the remaining negative demyelinating cases and all axonal CMT cases. The first decade of life was the most common period of disease onset. In all, 353 patients had demyelinating CMT, 39 had intermediate CMT, and 111 had axonal CMT. Pathogenic or likely pathogenic variants were identified in 197 index cases.The most common causative genes among probands were PMP22 (duplication) (n = 116, 58.88%), GJB1 (n = 23, 11.67%), MFN2 (n = 12, 6.09%), GDAP1 (n = 7, 3.55%), MPZ (n = 6, 3.05%), PMP22 (point mutation) (n = 6, 3.05%), NEFL (n = 3, 1.52%), SBF2 (n = 3, 1.52%), and SH3TC2 (n = 3, 1.52%). Other identified variants were ≤1% of index cases. This study provides further data on the frequency of CMT subtypes in a Brazilian clinical-based population and highlights the importance of rarer and previously undiagnosed variants in clinical practice.

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“…Currently, there are at least 103 GDAP1 mutations linked to CMT, out of which 68 are reported missense mutations [ 69 ]. The functional effects of several GDAP1 mutations have been studied in cells using neurons and Schwann cells or yeast models [ 7 , 10 , 70 , 71 ].…”

Section: Discussionmentioning

confidence: 99%

Structural insights into Charcot–Marie–Tooth disease‐linked mutations in human GDAP1

Sutinen

¹

,

Nguyen

²

,

Raasakka

³

et al. 2022

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Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral polyneuropathy in humans, and its different subtypes are linked to mutations in dozens of different genes. Mutations in gangliosideinduced differentiation-associated protein 1 (GDAP1) cause two types of CMT, demyelinating CMT4A and axonal CMT2K. The GDAP1-linked CMT genotypes are mainly missense point mutations. Despite clinical profiling and in vivo studies on the mutations, the etiology of GDAP1-linked CMT is poorly understood. Here, we describe the biochemical and structural properties of the Finnish founding CMT2K mutation H123R and CMT2K-linked R120W, both of which are autosomal dominant mutations. The disease variant proteins retain close to normal structure and solution behavior, but both present a significant decrease in thermal stability. Using GDAP1 variant crystal structures, we identify a side-chain interaction network between helices ⍺3, ⍺6, and ⍺7, which is affected by CMT mutations, as well as a hinge in the long helix ⍺6, which is linked to structural flexibility. Structural analysis of GDAP1 indicates that CMT may arise from disruption of specific intra-and intermolecular interaction networks, leading to alterations in GDAP1 structure and stability, and, eventually, insufficient motor and sensory neuron function.Inherited polyneuropathies are a genetically and clinically diverse group of neurodegenerative diseases affecting motor and sensory neurons in the peripheral nervous system (PNS) [1,2]. Mutations in dozens of genes expressed in the PNS cause Charcot-Marie-Tooth disease (CMT). Based on clinical findings, CMT can be classified into three forms: demyelinating, axonal, and intermediate [3,4]. The progress of CMT is linked to the hereditary pattern, whereby the autosomal recessive form has an earlier onset and more severe symptoms than the autosomal dominant form [5][6][7]. Understanding the molecular function of the proteins involved in the etiology of neuropathies is vital in efforts toward treatment and diagnosis.

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“…Currently, there at least 103 GDAP1 mutations linked to CMT, out of which 68 are reported missense mutations [67]. Both R120W and H123R are common mutations in European patients [7, 14, 68], and H123R was identified as a major founder mutation in the Finnish population [12, 13].…”

Section: Discussionmentioning

confidence: 99%

Structural insights into Charcot-Marie-Tooth disease-linked mutations in human GDAP1

Sutinen

¹

,

Nguyen

²

,

Raasakka

³

et al. 2022

Preprint

1

0

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Charcot-Marie-Tooth disease (CMT) is the most common inherited peripheral polyneuropathy in humans, and its different subtypes are linked to mutations in dozens of different genes. Mutations in ganglioside-induced differentiation-associated protein 1 (GDAP1) cause two types of CMT, demyelinating CMT4A and axonal CMT2K. The GDAP1-linked CMT genotypes are mainly missense point mutations. Despite clinical profiling and in vivo studies on the mutations, the etiology of GDAP1-linked CMT is poorly understood. Here, we describe the biochemical and structural properties of the Finnish founding CMT2K mutation H123R as well as CMT2K-linked R120W, both of which are autosomal dominant mutations. The disease variant proteins retain close to normal structure and solution behaviour, but both present a large decrease in thermal stability. Using GDAP1 variant crystal structures, we identify a side chain interaction network between helices α3, α6, and α7, which is affected by CMT mutations, as well as a hinge in the long helix α6, which is linked to structural flexibility. Structural analysis of GDAP1 indicates that CMT may arise from disruption of specific intra- and intermolecular interaction networks, leading to alterations in GDAP1 structure and stability, and eventually, insufficient motor and sensory neuron function.

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GDAP1 mutations are frequent among Brazilian patients with autosomal recessive axonal Charcot-Marie-Tooth disease

Cited by 8 publications

References 48 publications

Charcot‐Marie‐Tooth disease: Genetic profile of patients from a large Brazilian neuromuscular reference center

Charcot‐Marie‐Tooth disease: Genetic profile of patients from a large Brazilian neuromuscular reference center

Structural insights into Charcot–Marie–Tooth disease‐linked mutations in human GDAP1

Structural insights into Charcot-Marie-Tooth disease-linked mutations in human GDAP1

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