A potential rearrangement between CYP19 and TRPM7 genes on chromosome 15q21.2 as a cause of aromatase excess syndrome.
BACKGROUND
Aromatase excess syndrome (AES) is a rare hereditary autosomal dominant disorder characterized by increased extraglandular aromatization of steroids and presented with heterosexual precocity in males and isosexual precocity in females.


OBJECTIVE
The objective was to study the molecular basis of AES in a kindred with 16 affected subjects, both males and females.


METHODS
The propositus, currently a 17-year-old boy, presented with breast enlargement in the first year of life, which persisted thereafter. Investigations at the age of 7.5 yr revealed growth acceleration (height sd score, 2.8), puberty staging Tanner P1B3, testicular volume 6 ml, and bone age 13 yr. The hormonal data were compatible with increased conversion of androgens to estrogens, which was independent of gonadotropin secretion. In the affected adults, there were short stature (height sd score ranged from -3.7 to -2), gynecomastia in males, and macromastia in females.


METHODS
Linkage analysis was performed using a polymorphic tetranucleotide (TTTA) repeat marker at nucleotide position 682 of CYP gene, as well as two additional STS markers, D15S123 (CA)n and D15S209 (CA)n, located within genetic distance of less than 5 cM from CYP19 gene. Using RNA extracted from the breast tissue of the propositus, a 5'-rapid amplification of cDNA ends (RACE) was performed with gene-specific primers corresponding to exon 2 of CYP19 gene.


RESULTS
Linkage analysis with (TTTA)n, D15S123 (CA)n, and D15S209 (CA)n markers produced LOD scores 0.85, 1.5, and 1.17, respectively. 5'-RACE revealed a novel untranslated exon 1 composed by exon 1 of TRPM7 gene (Transient Receptor Potential Cation Channel, Subfamily M, member 7), which has ubiquitous expression.


CONCLUSIONS
5'-RACE finding points to a potential rearrangement between CYP19 and TRPM7 genes on chromosome 15q21.2 as a cause of AES.
Tiulpakov
Anatoly
A
Endocrinological Research Center, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russian Federation. ant@endocrincentr.ru
Kalintchenko
Natalya
N
Semitcheva
Tatyana
T
Polyakov
Alexander
A
Dedov
Ivan
I
Sverdlova
Polina
P
Kolesnikova
Galina
G
Peterkova
Valentina
V
Rubtsov
Petr
P
D000293:Adolescent; D001141:Aromatase / Q000235:genetics* / Q000378:metabolism*; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D002884:Chromosomes, Human, Pair 15; D005260:Female; D005262:Feminization / Q000235:genetics*; D015321:Gene Rearrangement; D008040:Genetic Linkage; D006177:Gynecomastia / Q000235:genetics*; D006801:Humans; D007473:Ion Channels / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008969:Molecular Sequence Data; D021141:Nucleic Acid Amplification Techniques; D011494:Protein Kinases / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases; D013577:Syndrome; D050053:TRPM Cation Channels
D007473:Ion Channels; D008565:Membrane Proteins; D050053:TRPM Cation Channels; D001141:Aromatase; D011494:Protein Kinases; D017346:Protein Serine-Threonine Kinases; C486583:TRPM7 protein, human