Galactosemia

Heredity (2010) 104, 148–154
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ORIGINAL ARTICLE

www.nature.com/hdy

The role of human demographic history in
determining the distribution and frequency of
transferase-deficient galactosaemia mutations
JM Flanagan1,2, G McMahon2, SH Brendan Chia2, P Fitzpatrick2, O Tighe2, C O’Neill1, P Briones3,
L Gort3, LKozak4, A Magee5, E Naughten1, B Radomyska6, M Schwartz7, JS Shin8, WM Strobl9,
LA Tyfield10, HR Waterham11, H Russell12, G Bertorelle13, JKV Reichardt14, PD Mayne1 and DT Croke2
1
Department of Pathology, The Children’s University Hospital, Dublin, Ireland; 2Molecular & Cellular Therapeutics, The Royal College
´
´
´
of Surgeons in Ireland, Dublin, Ireland; 3Institut de Bioquımica Clınica,Hospital Clınic and CIBERER, Barcelona, Spain, 4Center of
Molecular Biology & Gene Therapy, University Hospital Brno, Brno, Czech Republic; 5Northern Ireland Regional Genetics Service,
Belfast, UK; 6Department of Pediatrics, Institute of Mother and Child, Warsaw, Poland; 7Department of Clinical Genetics, University
Hospital Rigshospitalet, Copenhagen, Denmark; 8Children’s Hospital, University ofMunich, Munich, Germany; 9Center for Physiology
and Pathophysiology, Medical University of Vienna, Vienna, Austria; 10Southmead Hospital and University of Bristol, UK; 11Academic
Medical Centre, University of Amsterdam, The Netherlands; 12Centre for Cancer Research and Cell Biology, Queen’s University, Belfast,
`
UK; 13Dipartimento di Biologia, Universita di Ferrara, Ferrara, Italy and14University of Sydney, New South Wales, Australia

Classical or transferase-deficient galactosaemia is an
inherited metabolic disorder caused by mutation in the human
Galactose-1-phosphate uridyl transferase (GALT) gene. Of
some 170 causative mutations reported, fewer than 10% are
observed in more than one geographic region or ethnic group.
To better understand the population history of thecommon
GALT mutations, we have established a haplotyping system
for the GALT locus incorporating eight single nucleotide
polymorphisms and three short tandem repeat markers. We
analysed haplotypes associated with the three most frequent
GALT gene mutations, Q188R, K285N and Duarte-2 (D2), and
estimated their age. Haplotype diversity, in conjunction with
measures of genetic diversity and oflinkage disequilibrium,

indicated that Q188R and K285N are European mutations.
The Q188R mutation arose in central Europe within the last
20 000 years, with its observed east–west cline of increasing
relative allele frequency possibly being due to population
expansion during the re-colonization of Europe by Homo
sapiens in the Mesolithic age. K285N was found to be a
younger mutation thatoriginated in Eastern Europe and is
probably more geographically restricted as it arose after all
major European population expansions. The D2 variant was
found to be an ancient mutation that originated before the
expansion of Homo sapiens out of Africa.
Heredity (2010) 104, 148–154; doi:10.1038/hdy.2009.84;
published online 29 July 2009

Keywords: galactosaemia; Q188R; K285N; Duarte-2;haplotype; population genetics

Introduction
Galactosaemia is an autosomal recessive disorder of
carbohydrate metabolism that can be caused by a defect
in any one of the three enzymes involved in the
metabolism of galactose through the Leloir pathway.
The most common cause of galactosaemia, however, is
deficiency of the galactose-1-phosphate uridyl transferase (GALT) enzyme; this is sometimestermed as
transferase-deficient or classical galactosaemia (On-line
Mendelian Inheritance In Man no. 230400). The disease
usually presents in the neonatal period with symptoms
including vomiting, diarrhoea, failure to thrive, jaundice
and Escherichia coli sepsis. The incidence of transferasedeficient galactosaemia varies worldwide, ranging from
Correspondence: Dr JM Flanagan, Department of...