Loss of CLTRN function produces a neuropsychiatric disorder and a biochemical phenotype that mimics Hartnup disease

Abstract

Hartnup disease is an autosomal recessive condition characterized by neutral aminoaciduria and behavioral problems. It is caused by a loss of B 0 AT1, a neutral amino acid transporter in the kidney and intestine. CLTRN encodes the protein collectrin that functions in the transportation and activation of B 0 AT1 in the renal apical brush bordered epithelium. Collectrin deficient mice have severe aminoaciduria. However, the phenotype associated with collectrin deficiency in humans has not been reported.Here we report two patients, an 11-year-old male who is hemizygous for a small, interstitial deletion on Xp22.2 that encompasses CLTRN and a 22-year-old male with a deletion spanning exons 1 to 3 of CLTRN. Both of them present with neuropsychiatric phenotypes including autistic features, anxiety, depression, compulsions, and motor tics, as well as neutral aminoaciduria leading to a clinical diagnosis of Hartnup disease and treatment with niacin supplementation. Plasma amino acids were normal in both patients. One patient had low 5-hydroxyindoleacetic acid levels, a serotoninergic metabolite. We explored the expression of collectrin in the murine brain and found it to be particularly abundant in the hippocampus, brainstem, and cerebellum.We propose that collectrin deficiency in humans can be associated with aminoaciduria and a clinical picture similar to that seen in Hartnup disease. Further studies are needed to explore the role of collectrin deficiency in the neurological phenotypes. Nishitha R. Pillai and Delia Yubero shared joint first authorship.

CLTRN, Regulated by NRF1/RAN/DLD Protein Complex, Enhances Radiation Sensitivity of Hepatocellular Carcinoma Cells Through Ferroptosis Pathway

“…In mice, collectrin de ciency causes profound aminoaciduria involving both neutral and charged amino acids [16]. The expansion in the biochemical phenotype over that seen in Hartnup disease is thought to be associated with the additional role played by collectrin in the functioning of other renal amino acid transporters [17].…”

“…Currently, there are a limited number of studies on the function of CLTRN, and the major ndings are related to its role in the regulation of arterial pressure, nervous system, and blood glucose levels [17][18][19]. CLTRN has also been studied inextensively in tumors (only in kidney cancer) [20].…”

Inborn Errors of Metabolism Associated With Autism Spectrum Disorders: Approaches to Intervention

“…Loss of CLTRN protein and its functions results in a disorder of similar biochemical phenotype to Hartnup disease. CLTRN gene encodes the protein collectrin, a homolog of angiotensinconverting enzyme 2 (ACE2), which is involved in transportation and activation of B 0 AT1 protein in the renal epithelium (Singer and Camargo, 2011;Pillai et al, 2019).…”

Movement Disorders and Renal Diseases

“…However, the pathogenesis of these features is not clear because plasma amino acid levels were normal in the affected patients. 43 Channelopathies Epilepsy, Ataxia, Sensorineural Deafness, and Tubulopathy (EAST) Syndrome…”