Autosomal recessive single-gene diseases occur only in individuals withtwo mutant alleles of the disease-associated gene. Remember, for any givengene, a person inherits one allele from his or her mother and one allele from hisor her father. Therefore, individuals with an autosomal recessive single-genedisease inherit one mutant allele of the disease-associated gene from each oftheir parents. In pedigrees of families with multiple affected generations, autosomalrecessive single-gene diseases often show a clear pattern in which the disease "skips"one or more generations.
Phenylketonuria (PKU) is a prominent exampleof a single-gene disease with an autosomal recessive inheritance pattern. PKUis associated with mutations in the gene that encodes the enzyme phenylalaninehydroxylase (PAH); when a person has these mutations, he or she cannot properlymanufacture PAH, so he or she is subsequently unable to break down the amino acidphenylalanine, which is an essential building block of dietary proteins. As aresult, individuals with PKU accumulate high levels of phenylalanine in theirurine and blood, and this buildup eventually causes mental retardation andbehavioral abnormalities.
The PKU-associated enzyme deficiency was determined biochemically in the1950s—long before the PAH-encoding gene was mapped to human chromosome 12 andcloned in 1983. Specifically, Dr. Willard Centerwall, whose child was mentallyhandicapped, developed the first diagnostic test for PKU in 1957. Called the "wetdiaper" test, Centerwall's test involved adding a drop of ferric chloride to awet diaper; if the diaper turned green, the infant was diagnosed with PKU. Thewet diaper test was used to reliably test infants at eight weeks after birth;by this time, however, infants who were affected by PKU had already oftensuffered irreversible brain damage.
Thus, in 1960, Dr. Robert Guthrie, whose niece suffered from PKU andwhose son was also mentally handicapped, established a more sensitive methodfor detecting elevated phenylalanine levels in blood, which permitted adiagnosis of PKU within three days after birth. Guthrie's test used bacteria thatwere unable to make their own phenylalanine as messengers to report high bloodlevels of phenylalanine in an infant's blood sample obtained via heel prick. WithGuthrie's method, the phenylalanine-deficient bacteria were grown in mediatogether with a paper disk spotted with a drop of the infant's blood. If thephenylalanine levels in the blood were high, the bacteria would grow robustly,and a diagnosis of PKU could be made. Through the ability to discover thattheir child had PKU at such an early age, parents became able to respondimmediately by feeding their child a modified diet low in proteins andphenylalanine, thereby allowing more normal cognitive development. Guthrie'stest continues to be used today, and the practice of obtaining an infant'sblood sample via heel prick is now used in numerous additional diagnostictests.
Several other human diseases, including cystic fibrosis, sickle-cellanemia, and oculocutaneous albinism, also exhibit an autosomal recessiveinheritance pattern. Cystic fibrosis is associated with recessive mutations inthe CFTR gene, whereas sickle-cell anemia is associated with recessivemutations in the beta hemoglobin (HBB) gene. Interestingly, althoughindividuals hom*ozygous for the mutant HBB gene suffer from sickle-cellanemia, heterozygous carriers are resistant to malaria. This fact explains the higher frequency ofsickle-cell anemia in today's African Americans, who are descendants of a groupthat had an advantage against endemic malaria if they carried HBB mutations. Finally, oculocutaneousalbinism is associated with autosomal recessive mutations in the OCA2gene. This gene is involved in biosynthesis of the pigment melanin, which givescolor to a person's hair, skin, and eyes.
