Læknablaðið : fylgirit - 15.12.1994, Qupperneq 38

34
LÆKNABLAÐIÐ/FYLGIRIT 27
HRYGGRAUFARRANNSÓKNIR
E 39 Á MÖNNUM OG MÚSUM
Ólafur Jensson1, Guðmundur Bjarnason 2 og
Þórður Kristjánsson1.
’Erfðafræðideild Blóðbankans og 2Barnadeild
Landspítalans, Landspítalinn, Reykjavík.
A tæpum áratug hafa orðið miklar framfarir í
rannsóknum á þeim genum lífvera, sem stjórna þroskun
fóstra. Síðustu ár hafa rannsóknir á þroskunarstjóm-
genum músa verið mjög árangursríkar (1) og hvetjandi
fyrir þá sem fengist hafa við skyldar rannsóknir á
mönnum. Reynst hefur mögulegt að nota stökkbreytt
þroskunarstjórngen í músum til að bera kennsl á gen með
svipað hlutverk hjá mönnum (1).
Ánð 1985 kom prófessor R. Williamson til íslands og
stofnað var til samvinnu mill St. Mary’s Hospital í
London og erfðafræðideildar Blóðbankans um rannsóknir
á arfgengum klofnum gómi og tunguhafti í samvinnu við
lýtalækningadeild Landspítalans (2) og ári seinna einnig
um rannsóknir á fjölskyldu með arfgenga hryggrauf (3,
4). Stóð sú samvinna til 1990 en þá var samið um
rannsóknir á hryggrauf við erföafræðideild háskólans í
Nijmegen í Hollandi (5). Með því tengjumst við fjölþjóð-
legum rannsóknum á hryggrauf í músum og mönnum.
Efnivið í annan áfanga rannsóknarsamvinnu okkar við
Hollendinga var safnað í upphafi árs 1994. I tengslum við
hann fer fram ættarrannsókn á íslenskum fjölskyldum,
sem eignast hafa barn með hryggrauf.
Skyldleiki fjölskyldnanna var kannaður með forriti
sem skrifað var f Blóðbankanum. Tölvutæk gögn frá
Erfðafræðinefnd H.I. voru fengin um fjölskyldurnar og
tengsl þeirra athuguð með forritinu sem einnig breytir
gögnunum á vinnanlegt form fyrir Cyrillic. Cyrillic er
gagnagrunnur og teikniforrit sem auðveldar úrvinnslu og
framsetningu rannsóknargagna og erfðaefnisvinnu á
fjölskyldunum.
Víxlverkanir erfða og umhverfisþátta koma hvergi
skýrar fram en í áhrifum skaðlegra efna á þroskunar-
stjórngen og geta þau leitt til vanmyndunar líkamsvefja af
ýmsu tagi. Rannsóknir á slíkum genum er eitt af brýnustu
viðfangsefnum erfðafræðinnar á okkar tímum.
1. Kessel M & Gruss P. (1990) Murine Developmental
Control Genes. Science 249:374-379.
2. Moore GE et al. (1987) Linkage of an X-chromosome
cleft palate gene. Nature 326:91-92.
3. Jensson O et al. (1988) A family showing apparent X
linked inheritance of both anencephaly and spina bifida.
Medical Genetics 25:227-229.
4. Newton R et al. (1994) Linkage analysis of 62 X-
chromosomal loci excludes the X chromosome in an
Icelandic family showing apparent X-linked recessive
inheritance of neural tube defects. Clinical Genelics
45:241-249.
5. Hol FA et al. (1993) Exclusion mapping of the gene
for X-linked neural tube defetts in an lcelandic family-
Human Genelics 93:452-456.
E
40
WILSON DISEASE IN ICELAND: A CLINICAL
AND GENETIC STUDY.
Gordon R. Thomas1-2, Olafur Jensson4, Gunnar
Gudmundsson5, Leifur Thorsteinsson4 og Diane W.
Cox 1.2.3
'Research Institute, The Hospital for Sick Children,
2Department of Molecular and Medical Genetics and
^Department of Paediatrics, University of Toronto,
Toronto, Ontario, Canada. 4Department of Medical
Genetics, The Blood Bank and 5Department of
Neurology, National University Hospital, Reykjavik,
Iceland.
A survey of Wilson disease (WND) in Iceland has
revealed two large kindreds with affected individuals on
the island. We have used single strand conformation
polymorphism (SSCP) analysis and direct DNA
sequencing to screen the two families for mutations in the
ATP7B gene, which is defective in this diseasc. We have
also carried out studies of DNA haplotypes of
dinucleotide repeat polymorphisms (CA repeats) in this
region. The same mutation, a seven base pair deletion, is
present in both families (1) and clinical features are
similar.
A total of eight patients with Wilson disease have been
diagnosed in three sibships of two kindreds. Their clinical
symptoms, signs and biochemical and histological
investigation confirmed the diagnosis in all cases. Two
patients in family 2 died, a male age 23 and a female age
30. Three of the eight patients showed psychiatric
symptoms, uncommon manifestations of the disease.
Highly polymorphic microsatellite polymorphisms
(CA repeats) were typed in selected members of all three
sibships to determine the possible relationship of the
mutalions in both families. Two haplotypes are present on
the Wilson disease chromosomes in these families. Both
families share one of the haplotypes (11-5-13-7) and a
second is present in both sibships of family 2 (11-5-6-4).
Analyses of normal and WND chromosomes from other
populations have shown haplotype I to be present in other
Northern European populations while haplotype 2 appears
to be unique to WND chromosomes in Iceland.
SSCP analysis of exon 7 resulted in the detection of a
large band shift in the Icelandic patients . This shift was
not seen in 58 other patients with Wilson disease,
including seven of Scottish and one of Irish origin. Exon
7 was directly sequenced in DNA from patients and
unaffected spouses. A deletion of 7 base pairs was found
only in the patient samples . The deletion removes bases
2010 to 2016 of the coding region of the gene and results
in a stop codon at that site (1).
The direct PCR detection method works well for
identification of this mutation. The results are clear and
the analysis quick and easy to carry out. The haplotype
data and nature of the mutation support the existence of a
founder chromosome carrying the mutation. The Icelandic
mutation was not found in patients of Irish and Scottish
origins, who could share some of the Icelandic ancestral
genes.
I. Bull PC, Thomas GR, Rommens JM, Forbes JR
and Cox DW (1993) Thc Wilson disease gene is a
pulative copper transporting P-type ATPasc similar to the
Mcnkcs gene. Nalure Genetics 5: 327-337.