Their findings make genetic screenings and drug development for spastic paraplegia possible and can open the door for better diagnosis of chromosome 15 rearrangements, including deletions that cause Prader-Willi and Angelman syndromes, and duplications found in some cases of autism.
"Genes located in this part of chromosome 15 sit among a lot of genetic flotsam and duplicated regions we refer to as breakpoint regions. In the grand scheme of things, this is an evolutionary plus for humans, as these regions are prone to genetic recombination, duplication and other forms of gene shuffling that can add diversity to the human genome in the process of passing down chromosomes," said Robert D. Nicholls, D. Phil, a Professor in Penn's Departments of Psychiatry and Genetics. "In individuals, however, it can cause disease."
Nicholls and his colleagues announce their findings in two separate papers in the October issue of the American Journal of Human Genetics (available now online). The first paper describes how breakpoint regions on human chromosome 15 contribute to chromosome rearrangements in evolution and Prader-Willi and Angelman syndromes, and identifies four new genes - named NIPA1, NIPA2, CYFIPI, and GCP5 - in the most unstable part of chromosome 15. The second paper details how researchers linked a mutation in NIPA1 to families with hereditary spastic paraplegia.
"What we see here is two very important ways in which genetics can effect disease," said Nicholls. "Often inherited disease can stem from the mutation of a single gene, such as NIPA1 in spastic paraplegia. In the case of chromosome 15, disease can be caused by rearrangements such as occurs in Prader-Willi and Angelman. These are simply good genes in a bad neighborhood."
Scientists have known that Prader-Willi and Angelman can be attributed to the disruption of genes that sit near breakpoints - regions in the chromosome that are prone to being re-arranged by the cell's genetic machinery before the chromosomes are passed to their offspring. Prader-Willi and Angelman syndromes occur in one in every 12,000 to 15,000 births.
The two syndromes are genetically-related - yet separate - neurological disorders whose effects are determined based on which parent donates the faulty chromosome. Prader-Willi occurs when the chromosome is inherited from the father, and features mild cognitive impairment and morbid obesity; while Angelman is inherited from the mother, and is characterized by seizures, movement disorders, and severe mental retardation. Unlike the major genes associated with the two disorders, the function of the four genes discovered in the Nicholls lab are not dependent on which parent donated the chromosome.
"These are complex disorders that, because of these chromosomal breakpoints, don't play by the normal rules of genetics," said Nicholls. "The loss of these four genes on one chromosome may modify Prader-Willi and Angelman, but we still don't know exactly how." Nicholls realized that one of these four genes might also make a good candidate for the cause of spastic paraplegia, a hereditary condition marked by the progressive development of leg paralysis, which had also been mapped to this 'dangerous' region on chromosome 15.
The Penn researchers collaborated with John K. Fink, MD, a neurologist with the University of Michigan Health System and noted researcher of spastic paraplegia. Fink's laboratory was able to provide small DNA samples from several individuals of a family with spastic paraplegia and, of the four genes identified, Dr. Jing-Hua Chai in the Nicholls' laboratory first identified a NIPA1 gene mutation solely in individuals with spastic paraplegia. The Michigan laboratory completed the mutation screening and independently identified an identical mutation in a second family with spastic paraplegia. Altogether, these findings can expand the genetic diagnosis of the disease, before clinical onset as well as for families who wish to seek prenatal genetic counseling.
Funding for this research was provided through grants from the National Institutes of Health, the March of Dimes Birth Defects Foundation, and the Muscular Dystrophy Association.