The photoreceptor cell-specific nuclear receptor gene ( PNR ) accounts for retinitis pigmentosa in the Crypto-Jews from Portugal (Marranos), survivors from the Spanish Inquisition

Abstract

The last Crypto-Jews (Marranos) are the survivors of Spanish Jews who were persecuted in the late fifteenth century, escaped to Portugal and were forced to convert to save their lives. Isolated groups still exist in mountainous areas such as Belmonte in the Beira-Baixa province of Portugal. We report here the genetic study of a highly consanguineous endogamic population of CryptoJews of Belmonte affected with autosomal recessive retinitis pigmentosa (RP). A genome-wide search for homozygosity allowed us to localize the disease gene to chromosome 15q22-q24 (Zmax=2.95 at θ=0 at the D15S131 locus). Interestingly, the photoreceptor cell-specific nuclear receptor (PNR) gene, the expression of which is restricted to the outer nuclear layer of retinal photoreceptor cells, was found to map to the YAC contig encompassing the disease locus. A search for mutations allowed us to ascribe the RP of Crypto-Jews of Belmonte to a homozygous missense mutation in the PNR gene. Preliminary haplotype studies support the view that this mutation is relatively ancient but probably occurred after the population settled in Belmonte.

NR2E3mutations in enhanced S-cone sensitivity syndrome (ESCS), Goldmann-Favre syndrome (GFS), clumped pigmentary retinal degeneration (CPRD), and retinitis pigmentosa (RP)

“…Strikingly, homozygous carriers of the p.R311Q mutation have been diagnosed with ESCS [Bernal et al, 2008;Haider et al, 2000;Iannaccone et al, 2009;Khan et al, 2007;Nakamura et al, 2002;Wright et al, 2004], GFS [Bernal et al, 2008;Chavala et al, 2005;Pachydaki et al, 2009], CPRD [Sharon et al, 2003], and arRP [Bandah et al, 2009;Gerber et al, 2000]. The original cohort of patients diagnosed with arRP was not available for ERG analyses, but the reported clinical data was very similar to ESCS [Gerber et al, 2000;Weleber, 2002]. Additional patients were diagnosed with arRP based on the presence of clumped pigment deposits, but these were not of the bone-spicule type characteristic of RP [Bandah et al, 2009;Bernal et al, 2008].…”

“…NR2E3 mutations were identified in several patients affected by CPRD [Bernal et al, 2008;Sharon et al, 2003]. Additionally, a number of patients initially diagnosed with autosomal recessive RP (arRP) also carried NR2E3 mutations [Bandah et al, 2009;Bernal et al, 2008;Gerber et al, 2000].…”

Echoes from Sepharad: signatures on the maternal gene pool of crypto-Jewish descendants

“…[18][19][20][21][22][23] However, only a few reports have been published on Sephardic and crypto-Jewish descendants. [24][25][26][27][28][29][30] Recent analysis of paternal lineages in Iberia points to a high proportion of Jewish ancestry. 10 Nonetheless, this work assumes an oversimplified parental population scenario and recognizes 'alternative possible sources for lineages ascribed a Sephardic Jewish origin' .…”

In Pursuit of Synthetic Modulators for the Orphan Retina-Specific Nuclear Receptor NR2E3

“…[6][7][8][9][10][11] The physiological ligand for NR2E3 remains to be identified. Mutations in NR2E3 have been associated with several forms of retinal degeneration in human patients, including enhanced S-cone syndrome, [12][13][14] autosomal dominant 15,16 and recessive 17 forms of retinitis pigmentosa, Goldmann-Favre syndrome, 13 and clumped pigmentary retinal degeneration. 13 Several studies indicate that NR2E3 acts as a critical regulator of photoreceptor development 8,12,[18][19][20] where it may function as a repressor of cone-specific genes.…”