Overview

Gould Syndrome is a rare, genetic, multi-system disorder. Gould Syndrome is often characterized by abnormal blood vessels in the brain (cerebral vasculature defects), eye development defects (ocular dysgenesis), muscle disease (myopathy), and kidney abnormalities (renal pathology). However, the full spectrum is still uncharacterized and many aspects of the syndrome continue to emerge including abnormalities affecting the structure of the brain (cerebral cortical abnormalities) and lung (pulmonary) abnormalities.

Diagnosis

Gould Syndrome is diagnosed following a test revealing a  genetic variant in COL4A1 or COL4A2. If either parent also carries the mutation, it is considered inherited. If neither parent carries the mutation, it is considered de novo which means that the mutation is a new occurrence. In cases where the mutation is inherited, the carrier parent is often clinically mild or unaffected. This can occur if the carrier is a mosaic – which means that some cells carry the mutation while other cells do not. The degree of mosaicism is highly variable – ranging from only a small percent of cells with the mutation to nearly all cells carrying the mutation – and depends on the stage during development that the mutation occurred. It is important to discuss these concepts with a genetic counselor and understand their implications.

Disease Details

There are 28 different types of collagen in your body and mutations in the genes that encode these proteins lead to multiple, highly diverse diseases. For example, Type I collagen mutations cause Osteogenesis Imperfecta (brittle bone disease), Type II collagen mutations cause chondrodysplasias (defects of cartilage) and mutations in Type III collagen cause a form of Ehlers-Danlos Syndrome. The type IV collagens are encoded by six different genes (COL4A1, COL4A2, COL4A3, COL4A4, COL4A5 and COL4A6). Mutations in COL4A3, COL4A4 and COL4A5 were found in the early 1990's in patients with Alport Syndrome. These proteins have very restricted expression and Alport Syndrome primarily affects the kidneys with variable involvement of the eye and cochlea (hearing). Mutations in COL4A1 or COL4A2 causes Gould Syndrome and because these two proteins are found in almost all tissues nearly any organ can be affected.

In the human genome, there are 46 chromosomes. The X and Y chromosomes are called the sex chromosomes and the rest all are called 'autosomes'. COL4A1 and COL4A2 are on Chr. 13 and so Gould Syndrome is considered Autosomal and should affect males and females in equal numbers. We each inherit a full complement on autosomes from each of our parents giving us two copies of each gene. Only one copy of COL4A1 or COL4A2 needs to acquire a mutation in order to cause disease which means the mutations are Dominant – thus, Gould Syndrome is considered Autosomal Dominant. So far, it appears as though mutations in COL4A1 and COL4A2 lead to identical disease, however, for reasons that are not yet understood, mutations in COL4A2 are much less frequent than those in COL4A1.

Discovery & history

The syndrome is named for UCSF geneticist Douglas Gould, PhD, in recognition of his discovery of and his lab’s work on this rare, multi-system disorder. While using mutagenesis to develop new genetic models of glaucoma, he discovered a mutation in the gene encoding type IV collagen alpha 1 (COL4A1) in mice. We now know that mutations in COL4A1 and COL4A2 are pleiotropic and genetically complex and lead to a vast spectrum of seemingly unrelated human diseases. His lab now works to characterize these diverse pathologies and understand the molecular mechanisms that underlie disease with the hope that they may develop therapeutic interventions.