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SLITRK1 mutations in Trichotillomania

Trichotillomania (TTM) is a chronic behavioral disorder characterized by the irresistible urge to pull out one's hair, resulting in noticeable hair loss.1 Clinically, TTM is classified as an impulse-control disorder and believed to belong to the obsessive-compulsive (OCD) spectrum. Tourette's Syndrome (TS), also belonging to the OCD spectrum, was recently associated with mutations in the slit and trk like 1 (SLITRK1) gene.2 Abelson et al.2 identified a frameshift mutation and a 3′-UTR micro-RNA binding site variation in three independent TS families. The mother of one proband carried the SLITRK1 mutation and was diagnosed with TTM. Therefore, we hypothesized that sequence variation in SLITRK1 may also contribute to TTM not associated with TS.

We have ascertained 44 TTM families in which one or more individuals met DMS-IV criteria for TTM.3 Self-reports of frequency and duration of hair pulling, related psychiatric symptoms, family history, and blood were obtained from patients and family members under IRB-approved procedures by Duke University Medical Center.

We directly re-sequenced the complete SLITRK1 gene in the index cases of 44 TTM families. We identified two novel non-synonymous sequence changes that occurred in two independent TTM subjects of European descent (Figure 1). In family DUK14044, a G>A transition resulted in substitution of arginine for lysine; c.1751G>A, R584K. In a second family (DUK14002), only nine residues downstream, a serine was replaced by glycine; c.1777A>G, S593G (Figure 1b). These sequence variations were not detected in the other TTM cases. Interestingly, both changes occurred within a short distance between the second LRRCT domain and the transmembrane domain of SLITRK1 (Figure 1a). Mutations in this position may be associated with TTM in the absence of TS since the mutations reported by Abelson et al.2 was in a different part of the protein. We then designed Taqman genotyping assays and screened for the presence of these variations in a sample of 2192 non-TTM Caucasian controls. We controlled for the presence of these variations by using the two TTM patients as positive controls for the assays (primer and probe sequences are available from the authors upon request). We did not detect the altered genotypes in this sample. Thus, these sequence changes are strongly associated with the TTM phenotype (P=0.0004, Fisher's exact test).

Figure 1
figure1

Genetic organization of SLITRK1 and detected mutations in trichotillomania families. (a) A schematic of SLITRK1 with the detected mutations (green – new mutations in trichtillomania; black – reported changes in Tourette's syndrome: ^deletion, ^^var321 (2)). Colored bars represent conserved protein domains according to CCDB (LRR – leucine-rich repeat; LRRCT – leucine-rich repeat C-terminal domain; TM – transmembrane domain; miR-189 – micro RNA binding site). aa – amino acid, nt – nucleotides. (b, c) Pedigrees of the identified families and sequencing traces of controls and affected subjects. Overlapping PCR products covering the entire sequence of SLITRK1 were directly sequenced by applying the BigDye terminator reaction kit (Applied Biosystems, Foster City, USA), and then subjected to an ABI3730 sequencer (primers are available form the authors upon request). Arrows indicate the index patients. Black symbols – trichotillomania; open symbols – unaffected; shaded symbol – mood disorder/low self-esteem. (d) The two novel mutations are highly conserved across different species. Green – identified mutations; gray – conserved residues.

Individual II:1 of family DUK14044 was 38 years old and reported hair pulling since the age of nine (Figure 1b). She also picked at her skin and presented with motor tics. Although she had a history of depression, current self-reported mood on the Beck Depression Inventory was within normal limits. She had mild anxiety as evidenced by a slight elevation on the State Trait Anxiety Inventory. Her father (I:1) had no history of psychiatric disorder. Her mother (I:2), who is a mutation carrier, had a history of depression, low self-esteem, and fear of heights. However, there was no evidence of TTM.

The index case of family DUK14002 (II:1) was diagnosed with TTM at the age of nine (Figure 1c). Currently, at the age of 14, her TTM symptoms have remitted, but she twirls her hair and bites her nails. Based on self- and parent-report, there were no clinically significant mood, anxiety, or behavior problems. Her father, who was 46 years of age, was the mutation carrier. He was formally diagnosed with TTM and social phobia, and also has a history of bulimia. Self-ratings for mood disorders and general anxiety were not clinically significant. However, social anxiety symptoms were in the clinically significant range. His sister, who was not available for genetic testing, had also been diagnosed with TTM. She reported a history of anxiety and depressive disorders.

Of the 44 TTM nuclear families examined, two had SLITRK1 sequence variants, accounting for a frequency of 4.5%. Both changes presented with an extremely low allele frequency and occurred in a conserved region. The mutations also co-segregated with psychiatric conditions in their respective nuclear pedigrees (Figure 1b and c). In family DUK14044, the mother carried the mutation but had no apparent features of TTM. However, individuals affected with TTM tend to disguise the condition and a diagnosis might have been missed.4 Alternatively, the phenotypic penetrance is incomplete or SLITRK1 mutations may underlie an even wider spectrum of phenotypes.

In summary, our results confirm that rare variations in SLITRK1 result in disorders of the OCD spectrum. The prospect of genetic testing for these disorders will have substantial consequences for the clinical, research, and public perception of these and other psychiatric conditions.

References

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Correspondence to A Ashley-Koch.

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Zuchner, S., Cuccaro, M., Tran-Viet, K. et al. SLITRK1 mutations in Trichotillomania. Mol Psychiatry 11, 888–889 (2006). https://doi.org/10.1038/sj.mp.4001865

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