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The numerous recessive disorders which have been mapped using this technique since its description in 1987 are proof of its success. A summary o f the conditions which have been mapped using this technique is shown in Table 10.

The first disorder to be mapped using this approach was Wilson's disease which, astonishingly, was mapped in a large inbred Israeli-Arab family using a biallelic protein polymorphism (Frydman et al. 1985). The initial studies mapping Familial Mediterranean Fever (FMF), Werner's Syndrome and Bloom's syndrome (German et al. 1994; Schellenberg et al. 1992; Pras et al. 1992) all confirmed linkage which had been obtained using a ditferent approach. FMF and Werner's Syndrome were both mapped using large numbers of nuclear families and traditional mapping methods (Goto et al. 1992; Pras et al. 1992). Blooms Syndrome had been previously localised to chromosome 15 using chromosome microcell mediated transfer to correct the characteristic high sister chromatid exchange phenotype (McDaniel and Schultz, 1990).

The search for linkage to both alkaptonuria and Fukuyama CMD was facilitated by the identification of families with offspring affected by two recessive conditions (Toda et al. 1993; Pollack et al. 1993). In one consanguineous family the affected child had both alkaptonuria and neonatal severe hyperparathyroidism (NSHPT). In the second family there was coinheritance of alkaptonuria with sucrase-isomaltase deficiency in three children o f consanguineous parents. There is evidence that both NSHPT and the sucrase-isomaltase gene are localised 3q2 which is indeed where alkaptonuria

pigmentosa in one patient from a consanguineous Japanese family provided a candidate location for FCMD on chromosome 9q. Toda et al observed that all 15 affected individuals from 13 unrelated consanguineous families were homozygous at the D9S59 locus. The frequency o f homozygosity in 14 non-consanguineous patients was similar to that in the general population. Subsequent linkage analysis in all families proved linkage analysis o f the gene to a 7 cM region on chromosome 9q31- 33.

Disorder Reference Chromosomal location

Gene Cloned (year)

Ethnic origin o f Study

Population

Genetic Heterogeneity

Wilson's Disease Frv'dman et al. 1985 13 + (1993) Israeli-Arab

Spinal Muscular Atrophy , Gilliam et al. 1990 5 + (1994) -

Werners S\ndroine Schellenberg et al. 1992 8p + (1996) Japanese/Caucasian/Hispani

c

Familial Mediterranean Fever Pras et al. 1992 16p + (1997) North African / Iraqi -

Blooms syndrome German et al. 1994 15 + (1995) Non-Ashkenazi Jewish -

Alkaptonuria Poliak et al. 1993 _3p + (1996) Turkish -

Ataxia with Vitamin E Deficiency BenHamida et al. 1993 8q + (1995) Tunisian / Mediterranean -

Fukuyama Type Congenital Musular D \ strophy

Toda et al. 1993 9q31-33 Japanese

Bardet Biedl syndrome Kwitek-Black et a l l 993 16q - Bedouin Arab +

Sheffield et al. 1994 3p - Bedouin Arab

Familial Spastic Paraplegia Hentati et al 1994 8 Tunisian +

Merosin -Negative Congenital Muscular Dystrophy

Hillaire et al. 1994 6q2 + (1995) T urkislVMoroccan/

Tunisian

Table 10. Recessive Disorders mapped by Homozygosity Mapping

Disorder Reference Chromosomal location

Gene Cloned (year)

Ethnic origin o f Study Population Genetic Heterogeneity Neurosensor\/Nonsyndroniic Deafness Guilford et al 1994a Guilford et al 1994b Baldwin et al. 1995

Fukushima et al. 1995a

Fukushima et al l 995b DFNBl 13q DFNB2 l l q l 3 DFNB4 7q31 DFNB5 14q DFNB6 3p + (1997) + (1997) + (1998) Tunisian Tunisian Druze South hidian South Indian + Familial Persistenl Hyperinsulinaemic H\pogl>caemia o f infancy

Thomas et al. 1995 l i p Saudi-Arabian

La fora T \pe Progressive Myoclonic Epilepsy

Serratosa et al. 1995 6q Flispanic/

Palestinian/Iranian

Leber’s Congenial Amaurosis C am uzatetal. 1995 17p + (1996) Maglirebian/

Caucasian

+

Schw arlz-Jampel Syndrome Nichole et al. 1995 Ip34-p36 - Tunisian/South African -

Pycnodvsoslosis Gelb et al. 1995 lq21 + (1996) Arab -

Pendreds SvTidrome Sheffield et al. 1996 7q21-34

(7DFNB4)

+ (1997) Not stated

Pseudoh\poaldosleronism T \pe I Strautnieks et al. 1996 16pl2-13

12pl3-pter

+ (1996)

+

Israeli/Pakistani/Caucasian +

Table 10 cont. Recessive Disorders mapped by Homozygosity Mapping

The gene for ataxia with selective vitamin E deficiency was mapped using 12 affected individuals from three consanguineous Tunisian families(Ben Hamida et al. 1993). Taking into account the inbreeding loops in these families dramatically increased the initial lod score obtained. Consanguineous Tunisian families with three other autosomal recessive conditions were analysed simultaneously and thus served to estimate the heterozygosity o f the markers in the Tunisian population.

The advent of homozygosity mapping has been particularly important in localising

genes for nonsydromic autosomal recessive deafness (NSRD) which is the

predominant categoi*y of deafness worldwide (Guilford et al. 1994b). The difficulty in localising genes for NSRD arises from the extreme heterogeneity of this type of deafness. Homozygosity mapping has enabled genes to be localised using individual families(Baldwin et al. 1995; Fukushima et al. 1995; Fukushima et al. 1995; Guilford et al. 1994; Guilford et al. 1994). DFNBl and DFND2 were mapped using extended inbred kindreds from geographically isolated regions of Tunisia(Guilford et al. 1994a; Guilford et al. 1994a). However a single small nuclear family was sufficient to map DFNB5 (Fukushima et al. 1995a). Even within isolated populations identification of genes causing recessive deafness can be complicated by genetic heterogeneity. Baldwin et al found evidence for genetic heterogeneity for NSRD in two branches of a large Middle-Eastern Druze family (Baldwin et al. 1995).

A potential disadvantage of homozygosity mapping is that it may subsequently be difficult to narrow down the region of interest to a small enough area to begin positional cloning. For example the Lafora's epilepsy disease gene has been mapped to a 17cM region on chromosome 6 (Serratosa et al. 1995). However in at least two cases, merosin-deficient congenital muscular dystrophy and ataxia with selective vitamin E deficiency, the gene concerned has been identified rapidly by searching for mutations in candidate genes (Helbling-Leclerc et al. 1995; Oualichi et al. 1995).

The majority of other recessive disorders mapped by homozygosity mapping have so far proved to be genetically homogeneous. There are however some exceptions.

Linkage of Leber's Congenital Amaurosis to chromosome 17p was found in five families of Mahgrebian origin but not in families of French ancestry (Camuzat et al. 1995). This is perhaps not unexpected as genetic heterogeneity is seen in other retinal

dystrophies, for example retinitis pigmentosa (Rosenfeld et al. 1994). More

surprisingly, Hentati et al found evidence of more than one locus for a clinically homogeneous form o f recessive familial spastic paraplegia in the Tunisian population (Hentati et al. 1994). The heterogeneity might be explained by the fact that the Tunisian population is descended from ethnically diverse ancestors and clans have tended to remain insular favouring intrafamilial marriages. A similar situation may apply to the locus heterogeneity found for Bardet-Biedel syndrome in the Bedouin tribes (Sheffield et al. 1994; Kwitek-Black et al. 1993). Bardet Biedel Syndrome is a well defined clinical syndrome comprising mental retardation, obesity, retinitis

pigmentosa, post-axial polydactyly and hypogonadism (OMIM#209900). Loci on

chromosomes 16, and 3 were identified by studying two large inbred

multigenerational kindreds from unrelated Bedouin tribes (Sheffield et al. 1994; Kwitek-Black et al, 1993). A third locus on chromosome l l q was reported in a linkage study using nonconsanguineous American families although some families did not map to this locus (Leppert et al. 1994). With such a distinctive clinical phenotype genetic heterogeneity may indicate mutations in genes for different subunits of a complex protein or interacting proteins in a signalling cascade. This is the case for Pseudohypoaldosteronism Type 1 which has been mapped to two loci using 11 nuclear consanguineous families of mixed ethnic origin (Strautnieks et al. 1996). The disease mapped to chromosome 16pl2.2 in 6 families and to 12pl3.1-pter in the remaining five. The two chromosomal regions were known to harbour genes for the subunits of the epithelial sodium channel SCNNIB and SCNNIG on 16p and SCNNIA on 12p. A mutation in SCNNIG was subsequently found in three o f the 16p linked families (Strantmieks et al. 1996). All three families were of Indian origin and shared a common haplotype suggesting a founder mutation in this population.