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Vendemian, located about 15 miles from Montpellier in the southern Languedoc Roussillon region, nestles in a landscape whose slopes and plains are perfect for viticulture. Into this secluded wine-growing community came Nougaret, 'la Provencal', as he became known. It seems he married, had children and worked at his trade without incident until his death.
By 1907 his descendants numbered 2,076. How do we know this? Genetic research has shown that he was the progenitor of a form of congenital stationary night blindness (CSNB) that has persisted among the inhabitants of Vendemian for at least 12 generations. It is not known, however, whether Nougaret himself came from a branch of an earlier affected Provencal family.
CSNB is characterised by normal daytime vision and reduced, to varying degrees, vision in low ambient light levels. It is a non-progressive (hence 'stationary') condition that can be x-linked (mainly males affected), autosomal recessive or autosomal dominant.
The 'Nougaret' form, as it is now known, is of the latter type: parents are equally likely to transmit the disorder and offspring are equally likely to inherit it. If one parent has the defective gene, a child has a 50 per cent chance of inheriting the defect.
The Nougaret story begins
The outside world first became aware of the Nougaret family in 1831 when one Pierre Mirebagues, a 16-year-old French army conscript and fifth-generation descendant of Jean Nougaret, attempted to claim exemption from army service on account of his poor night vision.
He was suspected of malingering when the examining medical officer found he could read by candlelight, and was promptly enrolled for seven years' service. Fortunately, he was later re-examined and exempted from army service.
Mirebagues claimed that his father, grandfather and great-grandfather all had the same affliction. Intrigued, the military surgeon of Montpellier, M Gastè, told the story to a Belgian ophthalmologist acquaintance, Florent Cunier, who went to Vendemian to interview as many of the afflicted individuals as he could find there.
He arranged for a local antiquary, M Chauvet, to compile a genealogy of these inhabitants. By making extensive use of the parish records and village archives, and by talking to the villagers and collating the oral and written records of the village, Chauvet was able to establish Nougaret as the common ancestor of all the CSNB sufferers in the vicinity. His genealogy ran to 629 people, of whom 86 suffered from CSNB.
Although Cunier published his findings in 1838 and these brought the Nougaret story to a wider audience, the journal in which he published was not easily accessible.
A chance meeting
This, however, had the happy consequence of bringing together a triumvirate who were to join forces to investigate the case in more depth. At the turn of the 20th century the English ophthalmologist, Edward Nettleship, who was much concerned with inherited eye diseases, became interested in the Nougaret findings. But to obtain a copy of Cunier's paper, Nettleship had to apply to Ernst Fuchs, the famous Viennese ophthalmologist, as none was available elsewhere. After making his translation from the original French, Nettleship enlisted Dr H Truc, Professor of Ophthalmology at the University of Montpellier, to help with his investigation. Truc, in turn, asked M l'Abbé Alphonse Capion, Curé of Vendemian, for assistance.
Abbé Capion was to assemble a modern genealogy, a task that took two years, eventually producing the largest pedigree for any inheritance of any human condition. There were identified 2,076 descendants of Nougaret, of which 135 were known to have or have had night-blindness. Those affected comprised 72 males, 62 females and one sex unknown.
Truc and Nettleship concerned themselves with examining the external and internal appearance of the eyes of the living night-blindness sufferers. Their ophthalmoscopic and visual field examinations showed all cases to be of CSNB, as opposed to progressive retinitis pigmentosa (RP) or the result of any other disease. Nettleship's conclusions were in accordance with Cunier's and Chauvet's, and he published his findings with due acknowledgement to Abbé Capion in Trans Ophthal Soc UK (27:269-293) in 1907.
Nettleship became noted for his contributions to research into ocular albinism and RP ocular albinism Type I is known as Nettleship-Falls syndrome, and the Nettleship Medal of the Ophthalmological Society was named in his honour.
There were other subsequent attempts to update previous studies of the Nougaret CSNB, notably by Dejean in 1949. Unfortunately, by then the effects of two world wars and the introduction of modern modes of transport had resulted in opening up the Vendemian district and greater movement of people in and out of the region. With Vendemian no longer an isolated rural enclave it became much harder to trace Nougaret's later descendants.
Recent research
Modern advances in genetics have shifted the emphasis of research into the Nougaret CSNB. Recent research has looked at the mechanism of the condition. For the technically minded, in 1996 Dryja et al reported in Nature Genetics (Missuse Mutation in the Gene Encoding the Alpha Subunit of Rod Transduction in the Nougaret Form of Congenital Stationary Night Blindness, 13:358-360) that the condition is caused by a missense mutation in the gene encoding the a-subunit of rod transducin - the G-protein that couples rhodopsin to cGMP-phosphodiesterase in the phototransduction cascade. Thus rod transducin joins rhodopsin and the a-subunit of rod c-GMP phosphodiesterase to become the third unit of the rod phototransduction cascade where a defect is implicated as the cause of CSNB.
A 1998 study by Sandberg et al (Rod and Cone Function in the Nougaret Form of Congenital Stationary Night Blindness, Arch Ophthalmol 116:867-872) used electrophysiological techniques to analyse two 12th-generation members of the Nougaret family. Their findings suggest that rod function in this form of CSNB is not completely absent as had been previously thought. More recently still, in 2006, the biochemical mechanism of Nougaret CSNB was investigated via the study of a specially created transgenic 'Nougaret mouse'. The details are to be found in the paper of Moussaif et al (Phototransduction in a Transgenic Mouse Model of Nougaret Night Blindness, Neurosci 26(25):6863-6872). The mice were subjected to biochemical, electrophysiological and vision-dependent behavioural analysis. In summary, these mice were subjected to periods of light and dark adaptation during which their behaviour was monitored and after which their retinas were extracted and analysed. Two key deficiencies in the defective gene function were found to be the main mechanisms altering the visual signalling in the transgenic mice. These were responsible for the results of the analysis that revealed a unique phenotype of reduced rod sensitivity, and impaired activation and slowed recovery of the phototransduction cascade.
Never could the simple Provencal butcher Jean Nougaret have imagined the legacy he left to the inhabitants of little Vendemian, not to mention to science. Or that some mice, biochemically adapted by humans, would one day share his defective gene with his 2,076-plus descendants. ?
? David Baker is an independent optometrist
