A transthyretin mutation (Tyr78Phe) associated with peripheral neuropathy, carpal tunnel syndrome and skin amyloidosis

Magy, N.; Jj, Liepnieks; Gil, H; Kantélip, B.; Jl, Dupond; Kluve‐Beckerman, Barbara; Benson,

doi:10.3109/13506120308995254

Cited by 26 publications

(9 citation statements)

References 22 publications

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“…47,51,52 Notably, a tyrosine-to-phenylalanine mutation at position 78 of TTR affords an extremely amyloidogenic protein, comparable to the most aggressive L55P TTR variant. 51,52 Tyr78 is one of the key residues in the EF-helix region of TTR, forming hydrogen bonds with Asp18 of the AB loop. Interestingly, the D18G variant is also highly amyloidogenic.…”

Section: Implications For Amyloidogenic Mutants In and Around Region mentioning

confidence: 98%

Structural Insight into pH-Induced Conformational Changes within the Native Human Transthyretin Tetramer

Palaninathan

Mohamedmohaideen

Snee

et al. 2008

Journal of Molecular Biology

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Section: Implications For Amyloidogenic Mutants In and Around Region mentioning

confidence: 98%

Structural Insight into pH-Induced Conformational Changes within the Native Human Transthyretin Tetramer

Palaninathan

Mohamedmohaideen

Snee

et al. 2008

Journal of Molecular Biology

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“…It was hypothesized that Y78F exhibits the characteristics of an intermediate structure in the fibrillogenesis pathway and might represent an early event in TTR amyloidogenesis. Interestingly, this mutation designed in silico was found associated with peripheral neuropathy, carpal tunnel syndrome and skin amyloidosis [5]. …”

Section: Introductionmentioning

confidence: 99%

Presence of N‐glycosylated transthyretin in plasma of V30M carriers in familial amyloidotic polyneuropathy: an escape from ERAD

Teixeira¹,

Saraiva

2013

J Cellular Molecular Medi

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Familial amyloid polyneuropathy (FAP) is an autosomal dominant disease characterized by deposition of amyloid related to the presence of mutations in the transthyretin (TTR) gene. TTR is mainly synthesized in liver, choroid plexuses of brain and pancreas and secreted to plasma and cerebrospinal fluid (CSF). Although it possesses a sequon for N-glycosylation N-D-S at position 98, it is not secreted as a glycoprotein. The most common FAP-associated mutation is TTR V30M. In a screening for monoclonal antibodies developed against an amyloidogenic TTR form, we detected a distinct TTR with slower electrophoretic mobility in Western of plasma from carriers of the V30M mutation, not present in normal plasma. Mass spectrometry analyses of this slower migrating TTR (SMT) identified both wild-type and mutant V30M; SMT was undetectable upon N-glycosidase F treatment. Furthermore, SMT readily disappeared in the plasma of V30M - FAP patients after liver transplantation and appeared in plasma of transplanted domino individuals that received a V30M liver. SMT was also detected in plasma, but not in CSF of transgenic mice for the human V30M mutation. A hepatoma cell line transduced to express human V30M did not present the SMT modification in secretion media. Glycosylated TTR was absent in fibrils extracted from human kidney V30M autopsy tissue or in TTR aggregates extracted from the intestine of human TTR transgenic mice. Studies on the metabolism of this novel, glycosylated TTR secreted from FAP liver are warranted to provide new mechanisms in protein quality control and etiopathogenesis of the disease.

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“…Although the p.Tyr78Phe mutation is rare, it has been described once before in a 78-year-old French man of Italian origin who was affected with late-onset peripheral neuropathy in the lower limbs, bilateral carpal tunnel, and skin amyloidosis [9]. More than 100 pathogenic mutations leading to misfolding and formation of amyloid deposits have been detected in the TTR gene [10].…”

Section: Discussionmentioning

confidence: 99%

Tyr78Phe Transthyretin Mutation with Predominant Motor Neuropathy as the Initial Presentation

Riboldi

Ranieri

et al. 2011

Case Rep Neurol

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Transthyretin (TTR) amyloidosis, the most frequent form of hereditary amyloidosis, is caused by dominant mutations in the TTR gene. More than 100 mutations have been identified. Clinical manifestations of TTR amyloidosis are usually induced by extracellular amyloid deposition in several organs. The major neurological manifestation is motor-sensory neuropathy associated with dysautonomic impairment. Here, we describe a63-year-old man who came to our institution due to a suspected motor neuron disease. During a 4-year follow-up period, he underwent extensive clinical examination, electromyographic studies, sural nerve biopsy and TTR gene analysis by direct sequencing. Despite the predominant motor involvement, the detailed clinical examination also showed some mild sensory and dysautonomic signs. In addition, his clinical and family history included multiorgan disorders, such as carpal tunnel syndrome, as well as conditions with cardiac, renal, eye, and hepatic involvement. The sural nerve biopsy disclosed amyloid deposition, and the sequence analysis of the TTR gene detected a heterozygous Tyr78Phe substitution. The TTR gene variant found in our patient had only been described once so far, in a French man of Italian origin presenting with late-onset peripheral neuropathy and bilateral carpal tunnel syndrome. The predominant motor involvement presented by our patient is an uncommon occurrence and demonstrates the clinical heterogeneity of TTR amyloidosis.

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A transthyretin mutation (Tyr78Phe) associated with peripheral neuropathy, carpal tunnel syndrome and skin amyloidosis

Abstract: This TTR mutation (Tyr78Phe) is associated with peripheral neuropathy, carpal tunnel syndrome and skin amyloidosis. It is also associated with late onset of the disease.

Cited by 26 publications

References 22 publications

Structural Insight into pH-Induced Conformational Changes within the Native Human Transthyretin Tetramer

Structural Insight into pH-Induced Conformational Changes within the Native Human Transthyretin Tetramer

Presence of N‐glycosylated transthyretin in plasma of V30M carriers in familial amyloidotic polyneuropathy: an escape from ERAD

Tyr78Phe Transthyretin Mutation with Predominant Motor Neuropathy as the Initial Presentation

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