Evaluation of the ARMD1 locus on 1q25-31 in patients with age-related maculopathy: Genetic variation in laminin genes and in exon 104 of HEMICENTIN-1

M. Hayashi, J. E. Merriam, C. C.W. Klaver, J. Zernant, A. A. Bergen, R. T. Smith, S. Chang, J. C. Merriam, Rando Allikmets*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

36 Citations (Scopus)

Abstract

The age-related maculopathy (ARM) genetics program at Columbia University utilizes comprehensive genetic analysis of candidate genes in large case-control studies to determine genotypes associated with the ARM complex trait. Genes encoding laminins, a class of extracellular matrix proteins, represent attractive candidates for two reasons. First, the presence of laminins in the basal lamina of the retinal pigment epithelium (RPE), Bruch's membrane, and choriocapillaris suggests a possible role in the pathophysiology of ARM. Second, three laminin genes, LAMC1, LAMC2, and LAMB3, are located in the 1q25-31 region, within the previously mapped ARMD1 locus. The entire open reading frame of the three laminin genes was screened for variants by denaturing high-performance liquid chromatography (DHPLC) and direct sequencing in at least 92, and up to 368 ARM patients and matched unaffected controls. Sixty-nine sequence variants were detected in the 69 exons of the LAMC1, LAMC2, and LAMB3 genes. Screening of exon 104 of the recently proposed ARMDi gene, HEMICENTIN-1, residing in the 1q25-31 locus, did not detect the suggested causal variant, Q5345R, in 632 study subjects. Overall, we did not find statistically significant differences in the frequency of variants between ARM-affected individuals and age-matched controls. Four rare, non-synonymous, variants were detected in single cases of ARM patients. Our data on relatively limited numbers of study subjects do not suggest a significant role for genetic variation in the three laminin genes and in exon 104 of HEMICENTIN-1 in predisposing individuals to ARM. However, as in many instances in similar studies, involvement of rare amino acid-changing variants in a fraction of ARM cannot be ruled out.

Original languageEnglish
Pages (from-to)111-119
Number of pages9
JournalOphthalmic Genetics
Volume25
Issue number2
DOIs
Publication statusPublished - Jun 2004
Externally publishedYes

Bibliographical note

Funding Information:
We thank the patients, their families, and unaffected individuals for their participation. This study was supported in part by NIH Grant EY13435, Foundation Fighting Blindness, and Research to Prevent Blindness. The authors are grateful to Arne Bakker for expert technical assistance, to Dr. D.W. Schultz for kindly providing the control sample with the Q5345R mutation in the HEMICENTIN-1 gene, and to Drs. L. Del Priore and H. Cai for valuable advice.

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