Alkaptonuria: from humans to moulds and back.

Once upon a time The 'one gene, one polypeptide' dictum has an old pedigree. The story starts almos~ as soon as Mendel's laws were re-discovered. In 1902 Archibald E. Garrod l, on the advice of Bateson, interpreted alkaptonuria as a single recessive mendelian trait. Alkaptonuria is a very rare and not terribly serious condition in which a compound called 'alkapton' is excreted in urine. This compound is oxidized, causing darkening of urine (and nappies, wilere it is usually detected). In some patients, 'alkapton' also accumulates in the joints, causing ochronosis (staining of tissues, mainly cartilage) and arthritis. 'Alkapton' is homogentisic acid, a product of degradation of L-phenlyalanine and z-tyrosine. The title that Garrod gave his article 1 was appropriately: 'The incidence of alkaptonuria: a study in chemical individuality'. Garrod also introduced, here, the concept that individuals are expected to show slight variations in their metabolism, and that these should be subject to selective pressures. In 1908, Garrod delivered a series of Croonian lectures 2 with an even more prophetic title: 'Inborn errors of metabolism'. The second lecture dealt with alkaptonuria. All old stories are usually even older stories, and Garrod proposed that the f'wst description of alkaptonuria could be as old as 1584. A young historian of science short of a PhD project could exhume the archives of the Inquisition for further evidence. One can imagine that the ability of an otherwise healthy child to pass urine that turned as black as the blackest ink could have been very easily construed as witchcraft. In the Croonian lecture of 1908, Garrod correctly proposed that alkaptonuria could have one of two causes, 'Either the alkapton acid is a strictly abnormal product formed by the perverted metabolism of tyrosine.., or it is an intermediate product of normal metabolism which is usually completely destroyed and does not come to excretion, but which in alkaptonuria e s~pes destruction'. I like the expression 'perverted metabolism' although (because) it would be frowned upon by most of today's referees. Translated into today's jargon, Garrod wrote then that the alkaptonuric phenotype could be the result of either a gain-of-function or a loss-of-function mutation. Garrod condudes that the second explanation is the correct one. He quotes a number of experimental fact& including that non-alkaptonuric subjects (usually