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Endocrine-Related Cancer 16 (3) 1057 -1063     DOI: 10.1677/ERC-08-0287
Copyright © 2009 by the Society for Endocrinology
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Genome-wide scan identifies novel modifier loci of acromegalic phenotypes for isolated familial somatotropinoma

 S K Khoo1, R Pendek2, R Nickolov3, D C Luccio-Camelo4,5, T L Newton1, A Massie1, D Petillo1, J Menon6, D Cameron7, B T Teh1,8 and S-P Chan2

1 Laboratory of Cancer Genetics, Van Andel Research Institute, Grand Rapids, Michigan 49503, USA
2 Department of Medicine, University of Malaya Medical Centre, 50603 Kuala Lumpur, Malaysia
3 Department of Mathematics and Computer Science, Fayetteville State University, Fayetteville, North Carolina 28301, USA
4 Serviço de Endocrinologia, Hospital Universitário Clementino Fraga Filho, UFRJ, Rio de Janeiro 21949-590, Brazil
5 Department of Urology, University of Illinois at Chicago, Chicago, Illinois 60612, USA
6 Department of Medicine, Queen Elizabeth Hospital, 88586 Kota Kinabalu, Sabah, Malaysia
7 Department of Diabetes and Endocrinology, Princess Alexandra Hospital, Brisbane, Queensland 4102, Australia
8 NCCS-VARI Translational Cancer Research Laboratory, National Cancer Centre, Singapore, Republic of Singapore 169610

(Correspondence should be addressed to S K Khoo; Email: sok-kean.khoo{at}vai.org; S-P Chan; Email: spchan88{at}hotmail.com)

Isolated familial somatotropinoma (IFS) accounts for 18% of familial isolated pituitary adenoma (FIPA) cases. Recently, germline mutations of the aryl hydrocarbon receptor-interacting protein gene (AIP) have been found in families with pituitary adenoma predisposition, FIPA, and IFS. In this study, we investigate the AIP mutation status and perform a genome-wide scan to search for the modifier regions of acromegalic phenotypes in an IFS family of 31 aborigines from Borneo. Complete endocrine diagnosis and data could not be collected due to logistical and cultural reasons. AIP mutation screening was carried out by direct sequencing and the genome-wide scan was performed using 400 microsatellites. Non-parametric linkage analysis was performed to obtain the logarithm of odds (LOD) scores. A novel AIP frameshift mutation in exon 4 (c.500delC) (p.P167HfsX3) was identified in all members with acromegalic features, as well as in 15 members without acromegalic features, revealing incomplete penetrance of AIP. The data showed that patients with the same mutation may express acromegalic features of differing severity, suggesting the existence of modifier genes. The highest LOD score of 2.2 was obtained near D19S571 (19q13.41). We also found weak linkages on chromosomes 3q28, 8q12.1, and 21q22.13, with LOD scores of 1.1, 1.8, and 1.4 respectively. Our results show the first genome-wide scan that identifies novel modifier loci for acromegalic phenotypes in an IFS family. Identification of modifier loci may provide further insight into the disease mechanism and explain the clinical variability observed in its patients.






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