Contributions of MYOC and CYP1B1 mutations to JOAG

Abstract

Purpose: To investigate the role of MYOC and CYP1B1 in Iranian juvenile open angle glaucoma (JOAG) patients.

Methods: Twenty-three JOAG probands, their available affected and unaffected family members, and 100 ethnically matched control individuals without history of ocular disease were recruited. Clinical examinations of the probands included slit lamp biomicroscopy, intraocular pressure (IOP) measurement, gonioscopic evaluation, fundus examination, and perimetry measurement. Familial cases were classified according to the mode of inheritance. Exons of MYOC and CYP1B1 were sequenced, and novel variations assessed in the control individuals. Potential disease-associated variations were tested for segregation with disease status in available family members.

Results: The mode of inheritance of the disease in the families of four probands (17.4%) appeared to be autosomal dominant and in at least eight (34.8%) to be autosomal recessive. Four patients carried MYOC mutations, and an equal number carried CYP1B1 mutations. The MYOC mutations were heterozygous; two of them (p.C8X and p.L334P) are novel, and one codes for the shortest truncated protein so far reported. Autosomal recessive inheritance was consistent with inheritance observed in families of patients carrying CYP1B1 mutations. All these patients carried homozygous mutations.

Conclusions: MYOC and CYP1B1 contributed equally to the disease status of the Iranian JOAG patients studied. The contribution of the two genes appeared to be independent in that no patient carried mutations in both genes. The fraction of Iranian patients carrying MYOC mutations was comparable to previously reported populations.

Figure 1

Iranian JOAG pedigrees. (A) JG 102: Inheritance in this pedigree does not appear to be conclusively autosomal dominant because individuals of generation I are unaffected. Autosomal recessive inheritance seemed possible because of consanguinity and extensive inbreeding in village of residence. (B) JG 103 and (C) JG 111: Autosomal recessive inheritance is suggested in these two pedigrees because of multiple affected siblings born to unaffected parents who are first cousins. (D) JG 118: Autosomal dominant inheritance is suggested in this pedigree because affected individuals are observed in three consecutive generations. The affected individuals of the last two generations each had only one affected parent.

Figure 2

Novel mutations in MYOC. A: At the top, the sequence chromatogram is showing the heterozygous mutation, c.24C>A, which causes the codon change UGC to UGA, resulting in C8X; at the bottom, the chromatograph shows the wild type sequence. B: The top sequence chromatogram shows the heterozygous mutation, c.1001T>C, which is causing codon change CUU to CCU, resulting in L334P; the bottom chromatograph illustrates the wild type sequence.