The P28T Mutation in the GALK1 Gene Accounts for Galactokinase Deficiency in Roma (Gypsy) Patients across Europe

Hunter, Michael; Heyer, Évelyne; Austerlitz, Frédéric; Angelicheva, Dora; Nedkova, V.; Briones, Paz; Gata, Anna; Pablo, Rosaario de; László, A; Bosshard, Nills; Gitzelmann, R; Tordai, Attila; Kalmár, Lajos; Szalai, Csaba; Balogh, István; Lupu, Contantin; Corches, Axinia; Popa, G; Pérez-Lezaun, Anna; Kalaydjieva, Luba

doi:10.1203/00006450-200205000-00010

Cited by 38 publications

(28 citation statements)

References 18 publications

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“…1a. Motif I, having the sequence 38 Val-Asn-LeuIle-Gly-Glu-His 44 , abuts one side of the galactose moiety where the side chain of Glu 43 and the backbone peptidic nitrogen of His 44 participate in hydrogen bonding interactions with the C-6 hydroxyl group of the sugar. In human galactokinase, Motif II is formed by 136 Gly-Gly-Gly-Leu-Ser-Ser-Ser-Ala-Ser 144 and envelopes the phosphoryl moieties of the nucleotide.…”

Section: Resultsmentioning

confidence: 99%

“…This is further supported by biochemical data demonstrating that these sugars do not function as inhibitors of the galactokinase reaction thereby ruling out an explanation of non-productive binding (34). Interestingly, in the recent study of the sugar specificity exhibited by human galactokinase, it was shown that replacing Glu 43 with an alanine residue resulted in little effect on the steady state kinetics of the enzyme with its natural substrate, ␣-D-galactose. Hence, while the abolition of the C-6 hydroxyl group in arabinose and fucose results in no catalytic activity, deleting the side chain carboxylate of Glu 43 causes little change in the steady state kinetics of the enzyme.…”

Section: Structure Of Human Galactokinasementioning

confidence: 89%

“…As shown in Fig. 3, both the side chain of Glu 43 and the peptidic nitrogen of His 44 participate in hydrogen bonding interactions with O-6 of galactose. The loss of these two electrostatic interactions between the protein and either L-arabinose or D-fucose most likely results in the inability of the respective sugar to bind to the enzyme.…”

Section: Structure Of Human Galactokinasementioning

confidence: 99%

“…Interestingly, in the recent study of the sugar specificity exhibited by human galactokinase, it was shown that replacing Glu 43 with an alanine residue resulted in little effect on the steady state kinetics of the enzyme with its natural substrate, ␣-D-galactose. Hence, while the abolition of the C-6 hydroxyl group in arabinose and fucose results in no catalytic activity, deleting the side chain carboxylate of Glu 43 causes little change in the steady state kinetics of the enzyme. This contradiction can now be rationalized on the basis of the structure presented here.…”

Section: Structure Of Human Galactokinasementioning

confidence: 99%

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Molecular Structure of Human Galactokinase

Thoden

Timson

Reece

et al. 2005

Journal of Biological Chemistry

100

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Section: Resultsmentioning

confidence: 99%

Section: Structure Of Human Galactokinasementioning

confidence: 89%

Section: Structure Of Human Galactokinasementioning

confidence: 99%

Section: Structure Of Human Galactokinasementioning

confidence: 99%

See 2 more Smart Citations

Molecular Structure of Human Galactokinase

Thoden

Timson

Reece

et al. 2005

Journal of Biological Chemistry

100

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show abstract

“…The demographic growth rate was set at 1.32. 25 The allele frequency of LTBP2 p.R299X was 0.013 (Supplementary Table 3) and the proportion sampled was based on 600 000 population size. For p.E387K, whose distribution is limited to a specific geographic region (Figure 3), the allele frequency was set at 0.008 (based on the sub-isolate data in Sivadorai et al 17 ) and the estimates were carried out using a population size of 60K or 100K.…”

Section: Mutation Analysis In Affected Subjects and Familiesmentioning

confidence: 99%

LTBP2 and CYP1B1 mutations and associated ocular phenotypes in the Roma/Gypsy founder population

et al. 2010

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Primary congenital glaucoma (PCG) is a genetically heterogeneous autosomal recessive disorder, which is an important cause of blindness in childhood. The first known gene, CYP1B1, accounts for a variable proportion of cases in most populations. A second gene, LTBP2, was recently reported in association with a syndrome, in which glaucoma is secondary to lens dislocation. We report on the molecular and clinical profile of 34 families diagnosed as PCG, all originating from the Roma/ Gypsy founder population. Comprehensive sequencing analysis revealed a level of heterogeneity unusual for this population, with five CYP1B1 and one ancestral LTBP2 mutation accounting for B70% of patients (25 out of 37) and the remainder still unexplained. Homozygosity for the founder LTBP2 p.R299X mutation resulted in a more severe clinical phenotype and poorer outcome despite a markedly higher number of surgical interventions. The genetically homogeneous group of p.R299X homozygotes showed variable phenotypes (presumably also underlying pathogenetic mechanisms), wherein PCG proper with primary dysgenesis of the trabecular meshwork, and Marfan syndrome-like zonular disease with ectopia lentis and later onset secondary glaucoma are two extremes. The spectrum manifestations may occur in different combinations and have a different evolution even within the same sibship or a single patient. Preliminary observations on compounds with mutations in both CYP1B1-LTBP2 suggest that the observed combinations are of no clinical significance and digenic inheritance is unlikely. We provide a population genetics perspective to explain the allelic heterogeneity, comparing the history and geographic distribution of the two major founder mutations -p.R299X/LTBP2 and p.E387K/CYP1B1.

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Roma (Gypsies): Genetic Studies

Morar¹,

Azmanov²,

Kalaydjieva³

2013

Encyclopedia of Life Sciences

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The Roma, also known as Gypsies, are a transnational founder population, resembling a mosaic of socially and genetically divergent groups. Common origins from a small group of related founders result in sharing of maternal and paternal lineages and of ancient disease‐causing mutations across endogamous Romani groups in different countries. Genetic differentiation between groups, with an impact on genetic epidemiology, is the product of bottleneck events, random genetic drift and differential admixture and correlates with the migrational history of the Roma in Europe. Genetic studies are concordant with linguistic data, which provide support for the Indian origins of the Gypsies and suggest a single founding population that originated in north/northwestern India. Key Concepts: The Roma/Gypsies are a European population of Asian descent (most likely from the north‐western part of the Indian subcontinent), with origins documented by the presence of Indian maternal, paternal and autosomal lineages in parallel with admixture from autochthonous Europeans. The genetic history of the Roma is a string of bottleneck events starting with the founding of the proto‐Roma by a small group of Asian ancestors and followed by more recent population fissions reflecting the early migrations within Europe and the splits into multiple endogamous groups. The current genetic profile of the Roma has been shaped by founder effects, genetic drift and differential admixture. The social organisation, similar to the jatis of India, with limited gene flow between Romani groups, has resulted in marked genetic substructure. Autosomal recessive disorders occur at relatively high frequency and are usually characterised by limited mutational heterogeneity. They include disorders caused by mutations ‘imported’ from surrounding populations, which may reach high frequencies due to founder effect and drift as well as ‘private’ population‐specific mutations leading to novel rare disorders. The socially defined Romani group is the basic unit and starting point for medical genetic research due to limited diversity and common sharing of founder disease‐causing mutations between apparently unrelated families.

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The P28T Mutation in the GALK1 Gene Accounts for Galactokinase Deficiency in Roma (Gypsy) Patients across Europe

Cited by 38 publications

References 18 publications

Molecular Structure of Human Galactokinase

Molecular Structure of Human Galactokinase

LTBP2 and CYP1B1 mutations and associated ocular phenotypes in the Roma/Gypsy founder population

Roma (Gypsies): Genetic Studies

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