CLTRN – Hartnup Disease

Collectrin, encoded by CLTRN on Xp22.2, is the renal apical partner required for the neutral amino acid transporter B0AT1. Hartnup disease is characterized by neutral aminoaciduria and neurobehavioral abnormalities due to defective B0AT1. Although collectrin-deficient mice exhibit severe aminoaciduria, human phenotypes from CLTRN loss had not been described until recently (PMID:31520464).

Two unrelated male patients hemizygous for CLTRN deletions presented with autistic features, anxiety, depression, compulsions, motor tics, and neutral aminoaciduria leading to a clinical diagnosis of Hartnup disease treated with niacin supplementation (PMID:31520464). Plasma amino acid profiles were normal, and one patient showed low 5-hydroxyindoleacetic acid levels.

One patient carried a small interstitial deletion encompassing CLTRN on Xp22.2, while the other harbored a deletion of exons 1–3 of CLTRN; both lesions ablate collectrin function and segregate with disease in hemizygous males (PMID:31520464).

Functional evidence from coimmunoprecipitation and transport assays in Xenopus laevis oocytes demonstrates that B0AT1 activation in kidney requires collectrin, whereas intestinal expression depends on ACE2 (PMID:19185582). In collectrin-deficient mice, aminoaciduria recapitulates the biochemical hallmarks of Hartnup disease.

Collectrin expression in murine hippocampus, brainstem, and cerebellum aligns with the neuropsychiatric manifestations observed in patients, establishing a mechanistic link between CLTRN loss and central nervous system dysfunction (PMID:31520464).

Taken together, these data support an X-linked recessive association between CLTRN loss-of-function and a Hartnup-like neuropsychiatric disorder. Screening for CLTRN deletions should be considered in male patients with neutral aminoaciduria and neurobehavioral symptoms. Key take-home: CLTRN loss-of-function causes a Hartnup-like disorder amenable to niacin supplementation.

References

• American Journal of Medical Genetics Part A • 2019 • Loss of CLTRN function produces a neuropsychiatric disorder and a biochemical phenotype that mimics Hartnup disease. PMID:31520464
• Gastroenterology • 2009 • Tissue-specific amino acid transporter partners ACE2 and collectrin differentially interact with hartnup mutations. PMID:19185582

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