A New Locus for Autosomal Recessive Retinitis Pigmentosa (RP19) Maps to 1p13–1p21

Abstract

Autosomal recessive retinitis pigmentosa (arRP) is characterized by considerable allelic and nonallelic heterogeneity. Mutations have been described in the rhodopsin gene (RHO), the genes encoding the α and β subunits of rod phosphodiesterase (PDEA and PDEB) and the gene encoding the α subunit of the cGMP-gated channel (CNCG). In addition, linkage studies in single extended pedigrees have defined two new arRP loci, at 1q and 6p. In order to identify the disease gene in a Spanish consanguineous arRP family, a linkage analysis was undertaken. After testing 102 polymorphic markers, a significant positive lod score (Ζ max =3.64 at θ=0) was obtained with marker D1S188 at 1p13-p21, the same region where the Stargardt and fundus flavimaculatus (FFM) loci were previously defined. Exhaustive ophthalmologic examination of the patients clearly distinguished the disease from the Stargardt and FFM phenotypes, and revealed an atypical form of arRP with choroidal atrophy as a distinctive feature. 3Retinitis pigmentosa is a clinically and genetically heterogeneous group of retinal degenerations characterized by progressive loss of night and peripheral vision and, eventually, severe visual loss (9). As is the case of the autosomal dominant (adRP) and the X-linked (xlRP) forms of the disease, autosomal recessive retinitis pigmentosa (arRP) is characterized by allelic and nonallelic heterogeneity. Mutations cosegregating with the disease have been described in the rhodopsin gene (RHO) (15,24), the genes encoding the α and β subunits of rod phosphodiesterase (PDEA and PDEB, respectively) (3,10,21,28, 29) and the gene encoding the α subunit of the cGMP-gated channel (CNCG) (6). In addition, genetic linkage studies in single extended pedigrees have identified two new arRP loci, at 1q (18, 30) and 6p (14).Among the Spanish population, 39% of the RP pedigrees show an autosomal recessive pattern of inheritance (arRP) (2). Here we report the case of a Spanish consanguineous arRP family (M-33) with six out of seven sibs affected (Fig.1). Ophthalmologic examination of both parents revealed no manifestation of RP; the father (who died aged 72), showed no symptoms other than glaucoma, whereas the mother (aged 82) is totally asymptomatic. This fact, together with the consanguinity (second-cousin marriage), indicate an autosomal recessive pattern of inheritance. Clinical evaluation of the affected members suggested an aggressive form of the disease, with night blindness as the first symptom appearing in the first decade of life (mean age of onset, 8 years), followed by a decrease in visual acuity, starting at 14 years of age. Fundus examination and fluorescein angiographies (Fig.2) of the affected sibs in the fourth decade of life revealed papillary pallor, attenuated vessels, peripheral scattered pigmentation, bone spicule-like pigmentation reaching some areas of the macula and severe atrophy of the retinal pigment epithelium (RPE). At present, the older sibs show a complete scotoma while the youngest (around 45 years of age) still ...

Severe retinitis pigmentosa mapped to 4p15 and associated with a novel mutation in the PROM1 gene

“…It is distinguished from most forms of cone-rod dystrophy in which visual function at night is spared initially and for which some vision typically persists beyond the third to fourth decade (Evans et al 1995;Gregory-Evans et al 2000;Klevering et al 1999;Small and Gehrs 1996). Like this family, macular degeneration in association with RP has been reported in arRP caused by mutations in such genes as MERTK (McHenry et al 2004), RLBP1 (Burstedt et al 2001), and ABCA4 (Cremers et al 1998;Martinez-Mir et al 1997 as well as in arRP mapped to RP32 (Zhang et al 2005). Based on the clinical phenotype, the retinal dystrophy in this Pakistani family with p.Gln576X mutation is a severe form of retinitis pigmentosa.…”

Severe autosomal recessive retinitis pigmentosa maps to chromosome 1p13.3–p21.2 between D1S2896 and D1S457 but outside ABCA4

“…However, homozygous null mutations and two null alleles have also been identified in patients with STGD and CRD (Briggs et al 2001;Gerber et al 1998;Lewis et al 1999;Simonelli et al 2004). Macular degeneration has been described in most RP patients with ABCA4 mutations Fukui et al 2002;Klevering et al 2004;Martinez-Mir et al 1997. Some patients diagnosed as RP or RP-like had somewhat uncertain phenotypes (Klevering et al , 2004, or could not be excluded as having CRD (Klevering et al 2004),or were actually diagnosed as having STGD (Fukui et al 2002) or CRD (Paloma et al 2002) in earlier examinations.…”

“…Two arRP families with macular degeneration and ABCA4 mutations were independently assigned to ABCA4 region by linkage studies for candidate loci Klevering et al 1999;MartinezMir et al 1997MartinezMir et al , 1998. In one family, five of the six affected individuals were homozygous for markers extending more centromerically without a determined border (Martinez-Mir et al 1997). The second patients were classified as either RP-or CRD-like but were typical for neither disease.…”

“…1 and Table 3 which some vision typically persists beyond the third to fourth decade (Evans et al 1995;Gregory-Evans et al 2000;Klevering et al 1999;Small and Gehrs 1996). Like this family, macular degeneration in association with RP has been reported in arRP caused by mutations in such genes as MERTK (McHenry et al 2004), RLBP1 (Burstedt et al 2001) and ABCA4 Martinez-Mir et al 1997.…”

Integrated genetic and physical map of the 1q31→q32.1 region, encompassing the RP12 locus, the F13B and HF1 genes, and the EEF1AL11 and RPL30 pseudogenes

“…Mutations causing autosomal recessive retinitis pigmentosa (ARRP) have been described in the genes encoding the · and ß subunits of rod cGMP phosphodiesterase (PDE6A, PDE6B), rhodopsin, the rod cGMP gated cation channel, the cellular retinaldehyde-binding protein (CRALBP), the retinal pigment epithelium-specific protein (RPE65), an ATP binding transporter (ABCR), and the TULP1 gene (McLaughlin et al, 1993;Kumaramanickavel et al, 1994;Huang et al, 1995;Gu et al, 1997;Maw et al, 1997;Banerjee et al, 1998;Cremers et al, 1998;Hagstrom et al, 1998). The genes mapping to four additional ARRP loci on 1p (RP19), 1q (RP12), and 16p (RP22) remain to be identified , Shugart et al, 1995Martinez-Mir et al, 1997;Finckh et al, 1998). The RP12 locus was identified after whole genome scanning and linkage analysis in a large pedigree from a genetic isolate in The Netherlands.…”