Mutations in TTC37 Cause Trichohepatoenteric Syndrome (Phenotypic Diarrhea of Infancy)

Abstract

Background Trichohepatoenteric syndrome (THES) is an autosomal recessive disorder characterised by life-threatening diarrhoea in infancy, immunodeficiency, liver disease, trichorrhexis nodosa, facial dysmorphism, hypopigmentation and cardiac defects. We attempted to characterise the phenotype and elucidate the molecular basis of THES. Methods Twelve patients with classical THES from 11 families had detailed phenotyping. Autozygosity mapping was undertaken in 8 patients from consanguineous families using 250k single nucleotide polymorphism (SNP) arrays and linked regions evaluated using microsatellite markers. Linkage was confirmed to one region from which candidate genes were analysed. The effect of mutations on protein production and/or localisation in hepatocytes and intestinal epithelial cells from affected patients was characterised by immunohistochemistry. Results Previously unrecognised platelet abnormalities (reduced platelet α-granules, unusual stimulated alpha granule content release, abnormal lipid inclusions, abnormal platelet canalicular system and reduced number of microtubules) were identified. The THES locus was mapped to 5q14.3 – 5q21.2. Sequencing of candidate genes demonstrated mutations in TTC37, which encodes the uncharacterised tetratricopeptide repeat protein, thespin. Bioinformatic analysis suggested thespin to be involved in protein-protein interactions or chaperone. Preliminary studies of enterocyte brush-border ion transporter proteins (NHE2, NHE3, Aquaporin 7, Na/I symporter and H / K ATPase) showed reduced expression or mislocalisation in all THES patients with different profiles for each. In contrast the basolateral localisation of Na/K ATPase was not altered. Conclusion THES is caused by mutations in TTC37. TTC37 mutations have a multisystem effect which may be due to abnormal stability and / or intracellular localisation of TTC37 target proteins.

Diarrea crónica intratable asociada con diarrea fenotípica de la infancia (síndrome tricohepatoentérico)

“…El efecto de dicha mutación se piensa que es multisistémico aunque se han encontrado, con estudios de inmunofluorescencia confocal, inadecuada distribución o expresión disminuida de múltiples proteínas transportadoras apicales en enterocitos yeyunales. 4 Fabre y su grupo observaron que 6 de 15 individuos que mostraban características clínicas de diarrea fenotípica de la infancia o síndrome tricohepatoentérico no mostraron la mutación en TTC37; consideraron a TTC37 homólogo al gen SKI3 de levaduras y este es un componente clave de un complejo multiproteínico denominado Ski, requerido para la vigilancia exosomal de descomposición del ARN y la vigilancia de la expresión de la fidelidad genética del propio ARN. Buscaron mutaciones en el gen ortólogo humano de SKI3 que resultó en la identificación de mutaciones deletéreas en el gen SKIV2L en los seis individuos referidos.…”

An infant with trichohepato-enteric syndrome: case report

“…The estimated prevalence is 1/1,000,000 births. 1 44 cases have been published between 1982 and 2012. Literature reviewed showed that 9 clinical signs are associated with THE-S. [2][3][4][5][6][7][8][9][10][11][12][13][14][15] Three are constant: intractable diarrhea, facial dysmorphism and hair abnormality.…”

“…In case with abnormal antibody production, immunoglobulin administration may be required. 1 Patients with THE-S are also at increase risk of developmental delay, therefore early neurorehabilitative therapy should be started once developmental delay is identified.…”

“…Two are very frequent (more than 90%): IUGR and immunodeficiency; 2 are frequent: skin abnormalities and liver disease and 2 are rare: congenital cardiac defects and platelet anomaly. [1][2][3][4][5][6][7][8][9][10][11][12][13][14] The phenotypic presentation of THE-S is heterogeneous, and ranges from mild to severe form, which is characterized with long-term parenteral nutrition, and in some patients, typically it lasts for months to years, to achieve adequate nutrition and growth. 12 However, longterm parenteral nutrition should not be started in patients with concomitant liver disease.…”

“…A rare genetic disorder caused by mutation in SKIV2L or in TTC37. 1 The reviewed literature showed 9 clinical signs are associated with THE-S. 1 There are 3 signs that are always present: intractable diarrhea, facial dysmorphism and hair abnormality. In more than 90% of cases, patients have IUGR and immunodeficiency; other less frequent manifestations include: skin abnormalities, liver disease, congenital cardiac defects and platelet abnormalities.…”