Identification of a novel R552Q mutation in exon 13 of the β-subunit of rod phosphodiesterase gene in a Spanish family with autosomal recessive retinitis pigmentosa

Abstract

severe pulmonary and intestinal disease including ileus at birth and liver cirrhosis at the age 5 years, whereas the other one developed much better with only mild pulmonary changes. Clinical follow-up evaluation of our patient, a 5-year-old girl, was evocative of an intermediary status. Diagnosis of CF was established from positive sweat test at the age of 21 months. At the present time, she shows pulmonary disease and pancreatic insufficiency but not liver disease and develops well under therapy. REFERENCESDeufel A, Deufel T, Golla A, Achatz H, Bertele-Harms R, Roscher AA, Meitinger T (1994) Three novel mutations (1506s S466X, 1651A-T) in exon 10 Zielenski], Rozmahel R, Boron D, Kerem B, Gnelczak Z, Riordan JR, Rommens], Tsui L (1991) Genomic. DNA sequence of the Cystic Fibrosis Transmembrane of the Cystic Fibrosis Transmembrane Conductance regulator (CFTR) detected in patients of southern german descent. Hum Mutat 3:64-66.In 1994, a gene for hereditary breast and ovarian cancer (BRCAI) was isolated by positional cloning (Miki et al., 1994). Mutations in BRCAI are thought to be responsible for more than 80% of inherited breast and ovarian cancer (Easton et al., 1993). Women who harbour BRCAl germline mutations are estimated to have a 85-90% lifetime risk of breast cancer and an elevated risk of ovarian cancer.From the Max-Delbriick-Center (Berlin) collection of families with hereditary breast cancer (Easton et al., 1993) several families were selected for intensive investigation. Genomic DNA was prepared from blood samples and polymerase chain reaction (PCR)-amplified, using the primer pairs indicated by Friedman et al. (1994). The following SSCP analysis (Grade et al., 1994) revealed an aberrant banding pattern in exon 12 of the BRCAl gene in one family that could not be seen in other breast cancer families. Direct sequencing in both directions (sense and antisense strand) of the exon 12 PCR-amplified fragments was performed after alkali strand denaturation and separation of biotinylated primers with streptavidin-coated magnetic beads (Dynal, Oslo, Norway) using the Sequenase Terminator Single-Stranded DNA Sequencing Kit (Applied Biosystems, La Jolla, CA). A heterozygous two base pair (2-bp) deletion was identified in position 4282-4283 (reviewed, but not shown). This deletion leads to the creation of a TGA stop at codon 1389 and a predicted truncation of the BRCAl protein. 4282delAG could not be detected in the BRCA1 gene of 50 unrelated and unaffected individuals.One allele of the BRCAl gene is deleted in three members of the family. Familial history showed that mammary carcinomas occurred at an age of 35, 32, and 33, respectively. One patient suffered on ovarian cancer at an age of 56. This family is a clear example of an early-onset breast-ovarian cancer syndrome. ACKNOWLEDGMENTSWe thank I. Siimnich and H. Zeidler for technical assistance. This work was supported in part by MEC grant RRK13. REFERENCESEaston DF, Bishop T, Ford D, Crockford & the Breast Cancer Linkage Consortium (1993) Genetic linkage analy...

Mutations in USH2A in Spanish patients with autosomal recessive retinitis pigmentosa: high prevalence and phenotypic variation

“…1 Direct analyses of rhodopsin, the alpha and gamma subunits of rod cGMP-phosphodiesterase, periferin/RDS, rod outer segment membrane protein, recoverin, guanilate cyclase activating protein, S antigen, interstitial retinol binding protein, and NRL have failed to detect any disease causing mutation in non-syndromic ARRP Spanish families. Mutations in the beta subunit of the rod cGMP-phosphodiesterase gene, [2][3][4][5] in the ATP binding cassette receptor gene, 6 and in the TULP1 gene 7 account for a small percentage of Spanish ARRP families. These data indicate that genes other than these may be involved in the remaining families, emphasising the genetic heterogeneity of the disease and reinforcing the hypothesis that in ARRP a number of genes rather than one major gene will account individually for a small number of cases.…”

Study of the involvement of the RGR, CRPB1, and CRB1 genes in the pathogenesis of autosomal recessive retinitis pigmentosa

“…However, mutations in the beta subunit of the rod cGMP-phosphodiesterase gene, [8][9][10][11] in the ATP binding cassette receptor gene, 12 in the TULP1 gene, 13 in the alpha subunit of the rod cGMP gated channel, 14 and in the USH2A gene 15 have been detected in a small percentage of Spanish ARRP families. These data indicate that other genes play a part in the degeneration process of the retina in the remaining families.…”

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

“…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).…”