Mutations in the Myocilin Gene in Families With Primary Open-angle Glaucoma and Juvenile Open-angle Glaucoma

Abstract

To investigate the prevalence of myocilin (MYOC) mutations in Italian families with glaucoma and to determine the relationship of these mutations to primary open-angle glaucoma (POAG), juvenile openangle glaucoma (JOAG), and pigmentary dispersion glaucoma. Methods: Twenty-six patients with POAG were selected based on a positive family history of glaucoma. All patients and 210 relatives had an accurate clinical characterization. Main Outcome Measure: Each index patient was screened by single-stranded conformational polymorphism analysis for mutations in the MYOC gene. Results: A MYOC gene mutation was found in 2 families. In one family, a previously reported p.K423E mutation was transmitted from the index patient with POAG to the 2 sons with JOAG. In the second family, a p.C25R change, affecting the signal peptide, was transmitted from the index patient with POAG to the son with JOAG, but not to the son with pigmentary dispersion glaucoma. Conclusions: Clinical characterization of 2 families with MYOC gene mutations indicates that POAG and JOAG are the 2 sides of a continuum phenotypical spectrum due to a common molecular defect. On the other hand, our results confirm the different origin of pigmentary dispersion glaucoma. Clinical Relevance: Because MYOC gene mutations may be responsible for a fraction (2 [8%] of 26) of families with POAG/JOAG, a molecular genetic diagnosis should be included in the management of patients with glaucoma.

Chromosome 1q deletion and congenital glaucoma

“…5 Different types of MYOC mutations found in POAG make it hard to conclude whether the underlying mechanism is haploinsufficiency, gain of function, or a dominant negative effect. 6,7 Our patient is the first case of glaucoma with MYOC haploinsufficiency.…”

“…suggested that MYOC glaucoma is due either to insufficient levels of secreted MYOC or to compromised trabecular meshwork cell function caused by congestion of the trabecular meshwork secretory pathway 5 . Different types of MYOC mutations found in POAG make it hard to conclude whether the underlying mechanism is haploinsufficiency, gain of function, or a dominant negative effect 6,7 . Our patient is the first case of glaucoma with MYOC haploinsufficiency.…”

Chromosome 1q deletion and congenital glaucoma

“…5 Different types of MYOC mutations found in POAG make it hard to conclude whether the underlying mechanism is haploinsufficiency, gain of function, or a dominant negative effect. 6,7 Our patient is the first case of glaucoma with MYOC haploinsufficiency.…”

“…suggested that MYOC glaucoma is due either to insufficient levels of secreted MYOC or to compromised trabecular meshwork cell function caused by congestion of the trabecular meshwork secretory pathway 5 . Different types of MYOC mutations found in POAG make it hard to conclude whether the underlying mechanism is haploinsufficiency, gain of function, or a dominant negative effect 6,7 . Our patient is the first case of glaucoma with MYOC haploinsufficiency.…”

Association between primary open-angle glaucoma (POAG) and WDR36 sequence variance in Italian families affected by POAG

“…We previously demonstrated that in the Italian population about 6% of the familial cases with POAG has a mutation in MYOC gene 7. Conversely, no mutations were found in the OPTN gene 18.…”

Genetics of glaucoma

“…Towards that end, a commercial screening kit became available that screened for MYOC mutations, polymorphisms in the mt.1 promoter and, later, optineurin mutations. [65][66][67][68] Despite evidence that POAG in a black population is inherited via a major co-dominant gene, no mutations in the MYOC gene were found in the Barbados Family Study of Open-Angle Glaucoma despite the high prevalence of glaucoma in this population. For example, in the United Kingdom, a study of over 500 glaucoma patients found a mutation in MYOC in only 1.4% and the authors concluded that routine screening for MYOC mutations was not warranted.…”

Chromosome 1q deletion and congenital glaucoma

“…5 Different types of MYOC mutations found in POAG make it hard to conclude whether the underlying mechanism is haploinsufficiency, gain of function, or a dominant negative effect. 6,7 Our patient is the first case of glaucoma with MYOC haploinsufficiency.…”

“…suggested that MYOC glaucoma is due either to insufficient levels of secreted MYOC or to compromised trabecular meshwork cell function caused by congestion of the trabecular meshwork secretory pathway 5 . Different types of MYOC mutations found in POAG make it hard to conclude whether the underlying mechanism is haploinsufficiency, gain of function, or a dominant negative effect 6,7 . Our patient is the first case of glaucoma with MYOC haploinsufficiency.…”

Association between primary open-angle glaucoma (POAG) and WDR36 sequence variance in Italian families affected by POAG

“…We previously demonstrated that in the Italian population about 6% of the familial cases with POAG has a mutation in MYOC gene 7. Conversely, no mutations were found in the OPTN gene 18.…”

Genetics of glaucoma

“…Towards that end, a commercial screening kit became available that screened for MYOC mutations, polymorphisms in the mt.1 promoter and, later, optineurin mutations. [65][66][67][68] Despite evidence that POAG in a black population is inherited via a major co-dominant gene, no mutations in the MYOC gene were found in the Barbados Family Study of Open-Angle Glaucoma despite the high prevalence of glaucoma in this population. For example, in the United Kingdom, a study of over 500 glaucoma patients found a mutation in MYOC in only 1.4% and the authors concluded that routine screening for MYOC mutations was not warranted.…”

Chromosome 1q deletion and congenital glaucoma

“…5 Different types of MYOC mutations found in POAG make it hard to conclude whether the underlying mechanism is haploinsufficiency, gain of function, or a dominant negative effect. 6,7 Our patient is the first case of glaucoma with MYOC haploinsufficiency.…”

“…suggested that MYOC glaucoma is due either to insufficient levels of secreted MYOC or to compromised trabecular meshwork cell function caused by congestion of the trabecular meshwork secretory pathway 5 . Different types of MYOC mutations found in POAG make it hard to conclude whether the underlying mechanism is haploinsufficiency, gain of function, or a dominant negative effect 6,7 . Our patient is the first case of glaucoma with MYOC haploinsufficiency.…”

Association between primary open-angle glaucoma (POAG) and WDR36 sequence variance in Italian families affected by POAG

“…We previously demonstrated that in the Italian population about 6% of the familial cases with POAG has a mutation in MYOC gene 7. Conversely, no mutations were found in the OPTN gene 18.…”

Genetics of glaucoma

“…Towards that end, a commercial screening kit became available that screened for MYOC mutations, polymorphisms in the mt.1 promoter and, later, optineurin mutations. [65][66][67][68] Despite evidence that POAG in a black population is inherited via a major co-dominant gene, no mutations in the MYOC gene were found in the Barbados Family Study of Open-Angle Glaucoma despite the high prevalence of glaucoma in this population. For example, in the United Kingdom, a study of over 500 glaucoma patients found a mutation in MYOC in only 1.4% and the authors concluded that routine screening for MYOC mutations was not warranted.…”