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1.
Brain ; 146(5): 1844-1858, 2023 05 02.
Article in English | MEDLINE | ID: mdl-36314052

ABSTRACT

Charcot-Marie-Tooth (CMT) disease is one of the most common inherited neurological disorders, affecting either axons from the motor and/or sensory neurons or Schwann cells of the peripheral nervous system (PNS) and caused by more than 100 genes. We previously identified mutations in FGD4 as responsible for CMT4H, an autosomal recessive demyelinating form of CMT disease. FGD4 encodes FRABIN, a GDP/GTP nucleotide exchange factor, particularly for the small GTPase Cdc42. Remarkably, nerves from patients with CMT4H display excessive redundant myelin figures called outfoldings that arise from focal hypermyelination, suggesting that FRABIN could play a role in the control of PNS myelination. To gain insights into the role of FGD4/FRABIN in Schwann cell myelination, we generated a knockout mouse model (Fgd4SC-/-), with conditional ablation of Fgd4 in Schwann cells. We show that the specific deletion of FRABIN in Schwann cells leads to aberrant myelination in vitro, in dorsal root ganglia neuron/Schwann cell co-cultures, as well as in vivo, in distal sciatic nerves from Fgd4SC-/- mice. We observed that those myelination defects are related to an upregulation of some interactors of the NRG1 type III/ERBB2/3 signalling pathway, which is known to ensure a proper level of myelination in the PNS. Based on a yeast two-hybrid screen, we identified SNX3 as a new partner of FRABIN, which is involved in the regulation of endocytic trafficking. Interestingly, we showed that the loss of FRABIN impairs endocytic trafficking, which may contribute to the defective NRG1 type III/ERBB2/3 signalling and myelination. Using RNA-Seq, in vitro, we identified new potential effectors of the deregulated pathways, such as ERBIN, RAB11FIP2 and MAF, thereby providing cues to understand how FRABIN contributes to proper ERBB2 trafficking or even myelin membrane addition through cholesterol synthesis. Finally, we showed that the re-establishment of proper levels of the NRG1 type III/ERBB2/3 pathway using niacin treatment reduces myelin outfoldings in nerves of CMT4H mice. Overall, our work reveals a new role of FRABIN in the regulation of NRG1 type III/ERBB2/3 NRG1signalling and myelination and opens future therapeutic strategies based on the modulation of the NRG1 type III/ERBB2/3 pathway to reduce CMT4H pathology and more generally other demyelinating types of CMT disease.


Subject(s)
Charcot-Marie-Tooth Disease , Animals , Mice , Charcot-Marie-Tooth Disease/genetics , Guanine Nucleotide Exchange Factors/genetics , Mice, Knockout , Mutation , Neuregulin-1/metabolism , Schwann Cells , Sciatic Nerve/pathology , Sorting Nexins/genetics , Sorting Nexins/metabolism
2.
Eur J Med Genet ; 64(10): 104294, 2021 Oct.
Article in English | MEDLINE | ID: mdl-34352414

ABSTRACT

Cytoplasmic aminoacyl-tRNA synthetases (ARSs) are emerging as a cause of numerous rare inherited diseases. Recently, biallelic variants in tyrosyl-tRNA synthetase 1 (YARS1) have been described in ten patients of three families with multi-systemic disease (failure to thrive, developmental delay, liver dysfunction, and lung cysts). Here, we report an additional subject with overlapping clinical findings, heterozygous for two novel variants in tyrosyl-tRNA synthetase 1 (NM_003680.3(YARS1):c.176T>C; p.(Ile59Thr) and NM_003680.3(YARS1):c.237C>G; p.(Tyr79*) identified by whole exome sequencing. The p.Ile59Thr variant is located in the highly conserved aminoacylation domain of the protein. Compared to subjects previously described, this patient presents a much more severe condition. Our findings support implication of two novel YARS1 variants in these disorders. Furthermore, we provide evidence for a reduced protein abundance in cells of the patient, in favor of a partial loss-of-function mechanism.


Subject(s)
Developmental Disabilities/genetics , Failure to Thrive/genetics , Liver Diseases/genetics , Lung Diseases/genetics , Tyrosine-tRNA Ligase/genetics , Developmental Disabilities/pathology , Failure to Thrive/pathology , Female , Humans , Infant , Liver Diseases/pathology , Loss of Function Mutation , Lung Diseases/pathology
3.
J Pediatr Gastroenterol Nutr ; 68(5): 642-647, 2019 05.
Article in English | MEDLINE | ID: mdl-30628985

ABSTRACT

OBJECTIVES: High-resolution manometry (HRM) is the gold standard for diagnosis of esophageal motility disorders. However, clinical signs associated with these disorders are nonspecific, and it is difficult to correlate clinical signs with HRM data. The main objective of our study was to assess the positive predictive value (PPV) and negative predictive value (NPV) of each clinical sign, as well as their sensitivity and specificity in the diagnosis of esophageal motility disorders. METHODS: This is a bicentric retrospective cohort study based on HRM data collected between May 2012 and May 2016. The studied symptoms were weight loss, feeding difficulties, swallowing disorders, dysphagia, food blockages, vomiting, gastroesophageal reflux disease (GERD), belching, and respiratory symptoms. HRM data were analyzed according to the Chicago Classification (3.0). RESULTS: In total, 271 HRM data were analyzed, of which 90.4% showed abnormal results. HRM was well tolerated in 91% of the cases. The most common esophageal motility disorder was ineffective esophageal motility (38%). Weight loss was significantly associated (P = 0.003) with an abnormal HRM with a 96% PPV. CONCLUSIONS: With nonspecific clinical signs suggesting an esophageal motility disorder, weight loss was a predictive sign of abnormal HRM results. HRM was well tolerated in pediatric patients, and ineffective esophageal motility appears to be the most frequent motility disorder in our cohort, as already observed in adult patient studies.


Subject(s)
Esophageal Motility Disorders/diagnosis , Manometry/statistics & numerical data , Symptom Assessment/statistics & numerical data , Adolescent , Child , Child, Preschool , Female , Humans , Infant , Infant, Newborn , Male , Manometry/methods , Predictive Value of Tests , Reproducibility of Results , Retrospective Studies , Sensitivity and Specificity , Weight Loss , Young Adult
4.
Hum Mutat ; 39(6): 774-789, 2018 06.
Article in English | MEDLINE | ID: mdl-29527791

ABSTRACT

Tricho-Hepato-Enteric syndrome (THES) is a very rare autosomal recessive syndromic enteropathy caused by mutations of either TTC37 or SKIV2L genes. Very little is known of these two gene products in mammals nor of the pathophysiology of the disease. Since the identification of the genes, we have set up the molecular diagnostic of THES in routine, gathering a large cohort with clinical and molecular data. Here, we report the phenotype and genotype analysis of this cohort together with an extensive literature review of THES cases worldwide, that is, 96 individuals harboring mutations in one gene or the other. We set up locus-specific databases for both genes and reviewed the type of mutation as well as their localization in the proteins. No hot spot is evidenced for any type of mutation. The phenotypic analysis was first made on the whole cohort but is limited due to heterogeneity in clinical descriptions. We then examined the lab diagnostic cohort in detail for clinical manifestations. For the first time, we are able to suggest that patients lacking SKIV2L seem more severely affected than those lacking TTC37, in terms of liver damage and prenatal growth impairment.


Subject(s)
Carrier Proteins/genetics , DNA Helicases/genetics , Diarrhea, Infantile/genetics , Fetal Growth Retardation/genetics , Hair Diseases/genetics , Codon, Nonsense , Diarrhea, Infantile/pathology , Facies , Female , Fetal Growth Retardation/pathology , Hair Diseases/pathology , Humans , Male , Mutation , Phenotype
5.
Am J Hum Genet ; 102(3): 364-374, 2018 03 01.
Article in English | MEDLINE | ID: mdl-29429573

ABSTRACT

Despite the rapid discovery of genes for rare genetic disorders, we continue to encounter individuals presenting with syndromic manifestations. Here, we have studied four affected people in three families presenting with cholestasis, congenital diarrhea, impaired hearing, and bone fragility. Whole-exome sequencing of all affected individuals and their parents identified biallelic mutations in Unc-45 Myosin Chaperone A (UNC45A) as a likely driver for this disorder. Subsequent in vitro and in vivo functional studies of the candidate gene indicated a loss-of-function paradigm, wherein mutations attenuated or abolished protein activity with concomitant defects in gut development and function.


Subject(s)
Bone and Bones/pathology , Cholestasis/genetics , Diarrhea/genetics , Hearing Loss/genetics , Intracellular Signaling Peptides and Proteins/genetics , Loss of Function Mutation/genetics , Adolescent , Animals , Child, Preschool , Diarrhea/physiopathology , Family , Female , Fibroblasts/pathology , Gastrointestinal Motility , Humans , Infant, Newborn , Lymphocytes/pathology , Male , Pedigree , Phenotype , Syndrome , Young Adult , Zebrafish
6.
Am J Med Genet A ; 176(3): 727-732, 2018 Mar.
Article in English | MEDLINE | ID: mdl-29383842

ABSTRACT

Syndromic diarrhea/tricho-hepato-enteric syndrome (SD/THE) is a rare congenital enteropathy with seven main clinical features: intractable diarrhea of infancy, hair abnormalities, intrauterine growth restriction (IUGR), facial dysmorphism, immune dysfunction, and liver and skin abnormalities. SD/THE is caused by mutations in TTC37 or SKIV2L, two genes encoding components of the human SKI complex. To date, approximately 50 SD/THE patients have been described with a wide spectrum of mutations, and only one recurrent mutation has been identified in independent families. We present a detailed description of seven patients of Turkish origin with the same new mutation in TTC37: c.4572 G>A p.(Trp1524X). All seven patients were homozygous for this mutation and presented the typical clinical features of SD/THE, but with a milder presentation than usual. All seven patients were alive at the last follow-up. Four out of seven patients had no IUGR, and four patients never required parenteral nutrition. All patients presented a better growth rate than previously described in patients with SD/THE, with 4/7 above the 3rd percentile. The mutation is localized only forty amino acids from the end of TTC37, and as TTC37 is longer than the yeast SKI3, it is possible that a truncated protein is expressed and plays a reduced role in the SKI complex.


Subject(s)
Carrier Proteins/genetics , Diarrhea/congenital , Diarrhea/diagnosis , Mutation , Phenotype , Alleles , Child, Preschool , Family , Female , Genotype , Humans , Infant , Male , Pedigree , Siblings , Syndrome
7.
J Peripher Nerv Syst ; 17(2): 141-6, 2012 Jun.
Article in English | MEDLINE | ID: mdl-22734899

ABSTRACT

By sequencing of the FGD4 coding sequence in a cohort of 101 patients affected by autosomal recessive demyelinating Charcot-Marie-Tooth disease (CMT), we have identified two novel missense mutations in FGD4 in two patients from consanguineous descent: p.Arg442His in an Algerian patient and p.Met566Ile in a Lebanese girl. The patients present early onset, slowly progressive CMT, with drastic reduction of nerve conduction velocities. These mutations are the second and third missense mutations characterized in FGD4. They are likely to lead to conformational changes in the PH1 and FYVE domains.


Subject(s)
Charcot-Marie-Tooth Disease/genetics , Microfilament Proteins/genetics , Mutation, Missense , Adolescent , Child, Preschool , DNA Mutational Analysis , Female , Humans , Male , Pedigree , Reverse Transcriptase Polymerase Chain Reaction
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