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PubMed2001

The I1307K APC polymorphism: prevalence in non-Ashkenazi Jews and evidence for a founder effect.

A missense mutation within the APC gene, I1307K, was described in Ashkenazi individuals at risk for colorectal cancer (CRC) and in the general population. The anecdotal reporting of the occurrence of this mutation in some non-Ashkenazi individuals led us to hypothesize that within the Jewish people, the I1307K polymorphism may reflect a founder mutation, and that the mutation is not restricted to ethnic Ashkenazis. To test that notion, and to establish the occurrence rate of the I1307K polymorphism in non-Ashkenazi Jewish populations, we screened Iraqi and Moroccan Jews and consecutive Jewish CRC patients and performed haplotype analysis with APC-linked markers in two I1307K carrier families. We analyzed Jewish individuals: 210 Moroccans, 160 Iraqis, 148 Ashkenazi, and 349 CRC patients (227 Ashkenazi and 122 non-Ashkenazi). The mutation detection scheme included PCR followed by denaturing gradient gel electrophoresis (DGGE) or modified restriction analysis (MRA). Haplotypes were assessed using three intragenic and three flanking markers. The I1307K polymorphism was detected in 29/227 Ashkenazi (12.8%), 2/122 (1.6%) non-Ashkenazi CRC patients, and in 2 individuals each (approximately 1%) within the Moroccan and Iraqi populations. Allelic pattern analysis in all our I1307K carriers, revealed a common haplotype for the three intragenic markers tested, in all mutation carriers, regardless of ethnic origin. The I1307K polymorphism, therefore, exists in all ethnic Jewish populations: Ashkenazi and non-Ashkenazi, with or without colon cancer. Jewish I1307K mutation carriers share a common allelic pattern with APC-linked markers. This strongly supports the notion of a founder mutation for I1307K.

Adenocarcinoma↗
PubMed2002

Analysis of 15 primary open-angle glaucoma families from Australia identifies a founder effect for the Q368STOP mutation of myocilin.

Primary open-angle glaucoma (POAG) is a leading cause of blindness in the world. A number of mutations in the myocilin gene have been identified that predispose to glaucoma. The most frequent of these is the Glutamine368STOP (Q368STOP) mutation. It has been postulated that individuals with the Q368STOP mutation are derived from a common founder. To clarify this situation, we studied 15 unrelated POAG families who carried the Q368STOP mutation, from south eastern Australia. In one large family, nine affected and ten unaffected individuals were identified with the Q368STOP mutation. Closely linked polymorphic microsatellite markers were used to establish a disease haplotype in this family. Additional genotyping of markers in another 14 unrelated Q368STOP families revealed the presence of the same disease haplotype. These findings indicate that the Q368STOP mutation in all 15 families shared a common origin prior to the European settlement of Australia in the early 1800s.

Alleles↗
PubMed1995

Mitochondrial DNA of the Mauritian macaques (Macaca fascicularis): an example of the founder effect.

Macaque monkeys (Macaca fascicularis) were introduced to the island of Mauritius approximately 400 years ago. This study compares the mitochondrial DNA of macaques on Mauritius with those from Indonesia and the Philippines. The goal is to measure the amount of evolutionary change that has occurred in this isolated population over 400 years, and to address questions regarding the origin of the Mauritian founders. Amplification of the control region of the mitochondrial genome via the polymerase chain reaction yielded an 1800 base pair DNA fragment which was surveyed for variation using restriction endonucleases. Fifty-two macaques were separated into 17 haplotypes by mapping the restriction sites. No haplotypes were shared among the three populations, and only two closely related haplotypes appeared in the Mauritian sample. Nucleotide variation in the mitochondrial DNA in the Mauritian sample was 10-fold less than the Indonesian and Filipino samples. In contrast, allozyme data estimates of genetic diversity on Mauritius are similar to populations from the ancestral range. The evidence of the more severe bottleneck as measured by mitochondrial data may be explained in part by almost exclusive male dispersal in this species, and may support models of founder events in which rapid population growth prevents substantial loss of nuclear variation. The mitochondrial evidence supports the morphologically and historically based hypothesis that the original founders came from Indonesia.

Animals↗
PubMed2005

5alpha-reductase 2 gene mutations in three unrelated patients of Greek Cypriot origin: identification of an ancestral founder effect.

INTRODUCTION: 5alpha-Steroid reductase deficiency (5alphaSRD) is an autosomal recessive enzymatic deficiency. Mutations in the 5alpha-steroid reductase type 2 gene (SRD5A2) result in male pseudohermaphroditism caused by decreased dihydrotestosterone (DHT) synthesis--a key hormone of virilization of male external genitalia. AIM: To study for the first time patients from the Greek Cypriot population, describe their clinical characteristics, and identify the genetic mutations of the SRD5A2 gene. PATIENTS AND METHODS: Three unrelated patients with 46,XY karyotype born with ambiguous genitalia were examined. Patient 1 was raised as a girl and was diagnosed with partial androgen insensitivity syndrome, based on the clinical picture and incomplete laboratory investigation at the age of 4 years, and underwent gonadectomy. For this patient sequencing analysis of all five exons of the SRD5A2 gene and exons 2 to 8 of the androgen receptor (AR) gene was performed. Patients 2 and 3 were also born with ambiguous genitalia. The hCG test for these two patients was informative of 5alphaSRD, as it showed elevated T/DHT ratio after stimulation. Despite genetic counseling, both families decided to raise their infants as females because of severe under-virilization. Sequencing of the SRD5A2 gene was also completed for both patients. RESULTS: No mutations were found in the AR sequence for patient 1. Patients 1 and 3 were found homozygous for the mutation A/G at splice junction intron 1/exon 2 and patient 2 was found heterozygous for the same A/G substitution and also heterozygous for an additional mutation, Pro181Leu, in exon 3. CONCLUSIONS: The same mutation in the SRD5A2 gene was identified in three unrelated patients, in both homozygous and heterozygous form. This splice mutation was previously reported in Turkish patients. This underlying genetic abnormality may be characteristic for the Eastern Mediterranean region and is likely due to an ancestor effect.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗
PubMed2006

Mutations of DNAI1 in primary ciliary dyskinesia: evidence of founder effect in a common mutation.

RATIONALE: Primary ciliary dyskinesia (PCD) is a rare, usually autosomal recessive, genetic disorder characterized by ciliary dysfunction, sino-pulmonary disease, and situs inversus. Disease-causing mutations have been reported in DNAI1 and DNAH5 encoding outer dynein arm (ODA) proteins of cilia. OBJECTIVES: We analyzed DNAI1 to identify disease-causing mutations in PCD and to determine if the previously reported IVS1+2_3insT (219+3insT) mutation represents a "founder" or "hot spot" mutation. METHODS: Patients with PCD from 179 unrelated families were studied. Exclusion mapping showed no linkage to DNAI1 for 13 families; the entire coding region was sequenced in a patient from the remaining 166 families. Reverse transcriptase-polymerase chain reaction (RT-PCR) was performed on nasal epithelial RNA in 14 families. RESULTS: Mutations in DNAI1 including 12 novel mutations were identified in 16 of 179 (9%) families; 14 harbored biallelic mutations. Deep intronic splice mutations were not identified by reverse transcriptase-polymerase chain reaction. The prevalence of mutations in families with defined ODA defect was 13%; no mutations were found in patients without a defined ODA defect. The previously reported IVS1+2_3insT mutation accounted for 57% (17/30) of mutant alleles, and marker analysis indicates a common founder for this mutation. Seven mutations occurred in three exons (13, 16, and 17); taken together with previous reports, these three exons are emerging as mutation clusters harboring 29% (12/42) of mutant alleles. CONCLUSIONS: A total of 10% of patients with PCD are estimated to harbor mutations in DNAI1; most occur as a common founder IVS1+2_3insT or in exons 13, 16, and 17. This information is useful for establishing a clinical molecular genetic test for PCD.

Adolescent↗
PubMed2002

Leukocyte adhesion deficiency (LAD) type II/carbohydrate deficient glycoprotein (CDG) IIc founder effect and genotype/phenotype correlation.

Leukocyte adhesion deficiency (LAD) type II is a rare autosomal recessive syndrome characterized by recurrent infections, typical dysmorphic features, the Bombay blood phenotype and severe growth and psychomotor retardation. It is attributed to a general absence of fucosylated glycans on the cell surface. Three Arab Israeli patients and one Turkish child have been reported so far. The primary defect in a specific GDP-L-fucose transporter of the Golgi apparatus has been disclosed recently. All three children reported by us are homozygous for one single founder mutation, different from that reported in the Turkish child. The amount of mRNA of the GDP-L-fucose transporter in cells from Arab patients and their parents are comparable to controls. Genotype/phenotype correlation studies show that the two different mutations are distinguished by differences in response to fucose supplementation and in the clinical phenotypes.

Base Sequence↗
PubMed2001

Multiple founder effects in spinal and bulbar muscular atrophy (SBMA, Kennedy disease) around the world.

SBMA (spinal and bulbar muscular atrophy), also called Kennedy disease, is an X-chromosomal recessive adult-onset neurodegenerative disorder caused by death of the spinal and bulbar motor neurones and dorsal root ganglia. Patients may also show signs of partial androgen insensitivity. SBMA is caused by a CAG repeat expansion in the first exon of the androgen receptor (AR) gene on the X-chromosome. Our previous study suggested that all the Nordic patients with SBMA originated from an ancient Nordic founder mutation, but the new intragenic SNP marker ARd12 revealed that the Danish patients derive their disease chromosome from another ancestor. In search of relationships between patients from different countries, we haplotyped altogether 123 SBMA families from different parts of the world for two intragenic markers and 16 microsatellites spanning 25 cM around the AR gene. The fact that different SBMA founder haplotypes were found in patients from around the world implies that the CAG repeat expansion mutation has not been a unique event. No expansion-prone haplotype could be detected. Trinucleotide diseases often show correlation between the repeat length and the severity and earlier onset of the disease. The longer the repeat, the more severe the symptoms are and the onset of the disease is earlier. A negative correlation between the CAG repeat length and the age of onset was found in the 95 SBMA patients with defined ages at onset.

Exons↗
PubMed1999

A founder effect in the newfoundland population reduces the Bardet-Biedl syndrome I (BBS1) interval to 1 cM.

Bardet-Biedl syndrome (BBS) is a rare, autosomal recessive disorder; major phenotypic findings include dysmorphic extremities, retinal dystrophy, obesity, male hypogenitalism, and renal anomalies. In the majority of northern European families with BBS, the syndrome is linked to a 26-cM region on chromosome 11q13. However, the finding, so far, of five distinct BBS loci (BBS1, 1q; BBS2, 16q; BBS3, 3p; BBS4, 15q; BBS5, 2q) has hampered the positional cloning of these genes. We use linkage disequilibrium (LD) mapping in an isolated founder population in Newfoundland to significantly reduce the BBS1 critical region. Extensive haplotyping in several unrelated BBS families of English descent revealed that the affected members were homozygous for overlapping portions of a rare, disease-associated ancestral haplotype on chromosome 11q13. The LD data suggest that the BBS1 gene lies in a 1-Mb, sequence-ready region on chromosome 11q13, which should enable its identification.

Alleles↗