Un Novel Allel In Promotor Gene

Molecular Psychiatry (1999) 4, 97–99

Ó 1999 Stockton Press All rights reserved 1359–4184/99 $12.00

ORIGINAL RESEARCH ARTICLE

A novel allele in the

promoter region of the

human serotonin

transporter gene

E Michaelovsky1,2, A Frisch1,2, R Rockah1,2,

L Peleg2,3, N Magal2,4, M Shohat2,4 and

R Weizman2,5

1Laboratory of Biochemical Genetics, Felsenstein Medical

Research Center, Rabin Medical Center, Petah Tikva

49100, Israel; 2Sackler Faculty of Medicine, Tel Aviv

University, Tel Aviv, Israel; 3Genetic Institute, Sheba

Medical Center, Tel-Hashomer 52621, Israel; 4Institute of

Medical Genetics, Rabin Medical Center, Petah Tikva

49100, Israel; 5Tel Aviv Mental Health Center, Ramat-

Hatayassim, 9 Hatzvi St, Tel Aviv, Israel

Keywords: serotonin transporter; polymorphism; (5-

HTTLPR); allelic variation; Libyan Jews; association studies;

psychiatric disorders

The human serotonin transporter (hSERT) gene is a

promising candidate for mediating the genetic susceptibility

for various psychiatric conditions such as mood1

and obsessive-compulsive disorders.2 Two polymorphic

sites in this gene attracted much interest: a VNTR of 17-

bp repeats in intron two,3 and an insertion/deletion in

the 5¢-flanking promoter region (5-HTT gene-linked polymorphic

region-5-HTTLPR)4 creating a short (S) and a

long (L) allele. The 5-HTTLPR polymorphism is situated

in a GC-rich region composed of 20–23 bp repeating

units. The S and L alleles have 14 and 16 repeatelements

respectively. Positive associations of the 5-

HTTLPR polymorphism with mood disorders,5 anxietyrelated

personality traits,6 autism7 and late-onset Alzheimer’s8

disease have been published, although some

non replications were also reported.9,10 Here we report

a novel allele (termed LJ) in the 5-HTTLPR site. This

allele is longer than the L allele by 43 bp, has 18 repeat

units and contains two copies of the insertion/deletion

sequence arranged in tandem. The LJ allele was found

in individuals of Libyan and Tunisian Jewish origin but

not in Moroccan or Ashkenazi Jews.

The novel allele in the human serotonin transporter

gene promoter region (5-HTTLPR) was first discovered

in a Jewish family from Libya during an association

study involving this polymorphism and was denoted

LJ (Libyan-Jewish). Figure 1 shows the segregation of

5-HTTLPR alleles in the family. The LJ allele which

has a slightly higher molecular weight than the L allele

is present in a homozygote state in the mother and in

a heterozygote state in the daughter. In order to estimate

the frequency of this allele, several Jewish populations

of different ethnic origin were genotyped (Table

1). It can be seen that the LJ allele has an allelic frequency

of 2% and heterozygote frequency of 4% in 140

Figure 1 Various genotypes of the 5-HTTLPR polymorphism.

The short and the long alleles are present as homozygotes

(L/L) and heterozygotes (S/L). The Libyan-Jewish allele

(LJ) is present as homozygote in the mother (LJ/LJ) and heterozygote

in the daughter (S/LJ). M, molecular markers

(pBR322/MspI): 622 and 527 bp.

Libyan Jewish individuals and a lower frequency in

Tunisian Jews (allelic frequency 0.5%; heterozygote

frequency 1%). The allele was not found in 103 Moroccan

or 114 Ashkenazi Jews. The LJ allele was

sequenced, and its structure is depicted in Figure 2.

The LJ allele is composed of 18 repeat units as compared

with 16 and 14 units of the long and the short

alleles respectively. Repeat units 9–10 are the exact

duplication of repeats 7–8 which constitute the

insertion/deletion segment characteristic of the L

allele. Repeats 1–6 and 11–18 are common to all

three alleles.

The novel allele found in this study is a rare allele

that is specific to Jewish communities that originated

from Libya and Tunisia. It was not found either in Ashkenazi

or in Moroccan Jews. The Libyan and Tunisian

Jewish communities are small populations that

remained isolated until relatively recently. It is known

that several genetic diseases (familial Mediterranean

...