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ABSTRACT: Retinitis pigmentosa (RP) is the most common form of hereditary retinal degeneration. At least 32 genes and loci have been implicated in non-syndromic autosomal recessive RP. Progressive rod-cone degeneration is a canine form of autosomal recessive retinal degeneration, which serves as an animal model for human RP, and is caused by a missense mutation of the PRCD gene. The same homozygous PRCD mutation has been previously identified in a single human RP patient from Bangladesh. To date, this is the only RP-causing mutation of PRCD reported in humans.
The cause of the high incidence rate of autosomal recessive RP in an isolated Muslim Arab village in Northern Israel was investigated by haplotype analysis in affected families. The underlying mutation was detected by direct sequencing of the causative gene, and its prevalence in affected and unaffected individuals from the village was determined. Patients who were homozygotes for this mutation underwent ophthalmic evaluation, including funduscopy and electroretinography.
The identification of a novel pathogenic nonsense mutation of PRCD is reported. This founder mutation was found in a homozygous state in 18 patients from nine families, and its carrier frequency in the investigated village is 10%. The mutation is associated with a typical RP phenotype, including bone spicule-type pigment deposits and non-recordable electroretinograms. Additional findings include signs of macular degeneration and cataract. The identification of a second pathogenic mutation of PRCD in multiple RP patients confirms the role of PRCD in the aetiology of RP in humans.
Journal of Medical Genetics 08/2010; 47(8):533-7. · 6.36 Impact Factor
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ABSTRACT: In a Muslim Arab village, relatively isolated because of the preference of consanguineous marriages, we studied the fate of 12 mutations in 5 different genes. The study was based on carriers detected among relatives of affected patients and of carriers discovered in a random sample of 424 adults. Most of the mutations have been introduced by a carrier(s) originating from another village, but a few have been de novo events. Mutations that are very frequent in the entire village were introduced soon after the foundation of the village. Examples of such mutations are [GBJ2, 35Gdel] and [MEFV, M680I], with a carrier frequency of 7.8% and 6.2%, respectively. Many of the other mutations that are rare were introduced recently into the village and are frequent only among the descendants of the first couple carrying the mutation. For instance all the carriers of [ARSA, Q190H], responsible for metachromatic leukodystrophy, were found among the 218 descendants of a couple who were living in the village 4 generations ago. Since the village is typical for the region this study allows for some general conclusions to be drawn. In a population with a high degree of inbreeding the diagnosis of a single family with a patient(s) affected with a recessive disorder points to a recent event, while the finding of a rare disease in several families from an inbred population points to an older mutation. Mutations are often "exported" from one population to another by marriage. In the new inbred population this novel mutation will either be lost or will become frequent as the result of a founder effect. These observations are important for genetic counselling in the case of a recent mutation, since only the descendants of the founder couple are at risk, while in the case of older mutations the risk may be for the entire village. In the case of those frequent ancient mutations, the risk for a relative of an affected individual will be similar whether he marries a close relative or any random individual in the village.
Annals of Human Genetics 04/2007; 71(Pt 2):202-8. · 2.57 Impact Factor
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ABSTRACT: This study compares the effects of mutations in the gap junction protein connexin 26 (Cx26), on outer hair cells (OHCs), inner hair cells (IHCs) and auditory nerve/brainstem among carriers of these mutations. One hundred and twenty eight individuals, from a village with widespread consanguinity and congenital deafness, due to three Cx26 mutations, were selected among relatives of deaf persons, and divided into non-carriers, carriers of one mutation, homozygous to one mutation, or compound heterozygous carriers of two different mutations. Distortion product otoacoustic emissions (DPOAEs), auditory brainstem responses (ABRs) and audiometric evaluation were compared in these genetic groups. Hearing loss among homozygotes and compound heterozygotes was comparable and ranged from mild to profound. Most ABRs from these groups showed no responses or partial responses (peaks III, V) with prolonged latencies, but some individuals had all peaks at normal latencies. DPOAEs were absent, except sporadic responses. Carriers of one mutation had significantly smaller DPOAEs compared to non-carriers, although normal pure tone audiograms and ABRs were found in these groups. In conclusion, based on DPOAEs, Cx26 mutations may impact OHC function among carriers of one or two Cx26 mutations. IHC/nerve impairment among homozygotes and compound heterozygotes is variable. OHCs may be more susceptible to Cx26 mutations compared to IHCs and the auditory nerve and brainstem pathway activated by them.
Hearing Research 02/2003; 175(1-2):140-51. · 2.70 Impact Factor
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ABSTRACT: The purpose of this study was to examine whether outer hair cells (OHCs), inner hair cells and the brainstem auditory pathway are impaired due to a mutation in a gap junction protein, connexin 26 (Cx26), 35delG. Fifty-six individuals, from a village with widespread consanguinity and profound, non-syndromic congenital deafness, due to 35delG mutation, were selected among relatives of deaf people. The individuals were either non-carriers (n=20), heterozygous (n=20) or homozygous (n=16) for the mutation. Distortion product oto-acoustic emissions (DPOAEs) and auditory brainstem evoked potentials (ABEPs) in mutation non-carriers, in heterozygotes (carriers) and in subjects homozygous for the mutation were compared in addition to audiometric evaluation. Most deaf homozygotes had no DPOAEs, except some sporadic responses at 1000, 8000 and 10000 Hz. This was also observed in audiometry which showed profound hearing loss in most cases. Two cases were unique: one had moderate to severe hearing loss and the other had severe to profound hearing loss. A significant difference was found between non-carriers and carriers of 35delG: non-carriers had larger DPOAE responses than heterozygotes at all frequencies. The prevalence of responses got lower with higher frequencies in both groups, but between 6000 and 10000 Hz 50-70% of the carriers had no DPOAE responses, compared to 30-60% of non-carriers. In both groups responses diminished with age, but no significant interaction was found between age and the genetic group. ABEPs among homozygotes were variable: in most homozygotes ABEPs were absent or partial (waves III, V) with prolonged latencies, but two subjects had ABEPs within normal limits, in one ear. ABEPs were normal with no differences between carriers and non-carriers. We suggest that OHC function is affected by the 35delG mutation in Cx26. In addition, the hearing of carriers of this mutation may be impaired at very high frequencies (8000-10000 Hz), which are not assessed in routine audiometry or ABEP testing.
Hearing Research 02/2002; 163(1-2):93-100. · 2.70 Impact Factor
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ABSTRACT: Sex chromosome aneuploidy (SCA), when detected in amniocentesis, is usually an unexpected result of a test carried out for another purpose. For most SCAs, the prognosis is milder and less predictable than trisomy 21, and therefore parents are faced with a difficult decision regarding the option of pregnancy termination. While studies from Europe and the USA report a declining trend in termination rates for SCA, our local experience is different. During the period 1989-1998, we diagnosed 60 SCA (including mosaics) in 20 106 amniocenteses (0.29%) and 48 (80%) of these pregnancies were terminated, a significantly higher proportion than has been reported in Europe and the USA. The present study shows that the difference between our experience and others' may be related to differences in cultural norms and values. Thirty women were interviewed, of whom 23 terminated and seven continued the pregnancy. Interview analyses showed that the main reason behind the decision to terminate the pregnancy was associated with the parents' fear of non-specific abnormality of the child, and concerns about abnormal sexual development. Although genetic counseling practised in our center aims to be non-directive, 56% of the women reported that the counseling was either directive towards termination, or that they at least felt that the counselor's attitude was pro-termination. Most women (93%) reported themselves as having come to terms with their decision.
Prenatal Diagnosis 07/2001; 21(6):461-5. · 2.11 Impact Factor
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ABSTRACT: The screening program in Israel for Tay-Sachs disease has proven very successful, giving Jewish couples a choice not to have affected children. The technology of carrier detection is now possible in several other severe genetic diseases that are relatively frequent among Jews. Due to the current confusion, a policy is needed to determine how the TSD screening program should be continued in the Israeli Jewish population. We propose that such a screening program include only mutations agreed by consensus as causing a disease severe enough to warrant the possibility of therapeutic abortion. We also propose that general screening include only mutations that are relatively frequent, taking into account the carrier frequencies in the Israeli Jewish population.
The Israel Medical Association journal: IMAJ 10/2000; 2(9):665-7. · 1.02 Impact Factor
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ABSTRACT: Autosomal recessive diseases are common in the Arab population of Israel, mostly as a result of the high rate of consanguinity. They represent a major factor in the mortality and morbidity of the population. Since the distribution of genetic disorders in this population is not uniform, the present study was performed to determine the frequency and impact of recessive disorders within a single village. We demonstrate the existence of at least 19 autosomal recessive disorders in a village of about 8,600 inhabitants chosen at random. Since most of the disorders were chronic, the prevalence of recessive conditions in the village at the time of the study was at least 1/70, leading to a very high burden to the population and the health services.
American Journal of Medical Genetics 07/2000; 92(5):343-5.
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Molecular Genetics and Metabolism 04/2000; 69(3):169-80. · 3.19 Impact Factor
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ABSTRACT: Metachromatic leukodystrophy is a lysosomal storage disease caused by the deficiency of arylsulfatase A. Here we describe a hitherto unknown arylsulfatase A allele carrying a E312D missense mutation and characterize the effects of this and three previously described missense mutations, G86D, Y201C, and D255H, on arylsulfatase A. In transfection experiments no enzyme activity can be expressed from arylsulfatase A cDNAs coding for the D255H substituted enzyme, whereas Y201C and E312D mutations were associated with low amounts of residual enzyme activity. All amino acid substitutions lead to a decreased stability of the mutant enzyme, and metabolic labeling experiments indicated that except for the E312D substitution the mutations cause arrest of the mutant arylsulfatase A polypeptides in a prelysosomal compartment.
American Journal of Medical Genetics 04/2000; 91(1):68-73.
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J Zlotogora
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ABSTRACT: Several autosomal recessive disorders are present in high frequency in isolated populations because of either multiple allelic mutations or mutations in different genes. These observations are best explained by selection, which may be an important mechanism in the determination of the distribution of genetic disorders.
American Journal of Medical Genetics 12/1998; 80(3):266-8.
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J Zlotogora
Clinical Genetics 07/1998; 53(6):423-5. · 3.13 Impact Factor
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American Journal of Medical Genetics 05/1998; 77(1):79-80.
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J Zlotogora
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ABSTRACT: Mosaicism in germ cells has been recognized, over the past few years, as an important and relatively frequent mechanism at the origin of genetic disorders. There are two possibilities for the existence of such a mosaicism: one is that the mutation occurs in a germ cell that continues to divide. The other possibility is that the mutation occurs very early in a somatic cell before the separation to germinal cells and is therefore present both in somatic and germinal cells. Depending on various factors, such as the gene involved and/or the degree of mosaicism, the carrier of a somatic and germline mosaicism may be asymptomatic or may present with various symptoms of the disease. There are still relatively few reports in the literature in which the origin of germ-line mosaicism has been analyzed; nevertheless, they allow for a better insight into the mechanisms involved. In some diseases, such as osteogenesis imperfecta, new mutations are often present as asymptomatic somatic and germline mosaicism in one of the parents of the propositus. In other disorders, such as neurofibromatosis, somatic mosaicism is very rare in the parents of the propositus, perhaps since such mosaicism causes clinical symptoms. These differences are particularly important for genetic counseling in order to evaluate the risk for another affected child after the birth of the propositus.
Human Genetics 05/1998; 102(4):381-6. · 5.07 Impact Factor
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ABSTRACT: Since, at least in the near future, prenatal testing and abortion of affected fetuses will remain the main way of the prevention of genetic diseases, knowledge about the way of its acceptance in different cultures is important. The Israeli population includes two major groups: Jewish and Arabs, but while there is wide experience about the Jewish population and its attitude towards prenatal testing, little is known about the Arab population. This knowledge is particularly important, since genetic disorders are relatively frequent in the Arab world (Teebi and Farag, 1997). From 1992 to 1996, 816 prenatal tests were performed in our department on Arab women [143 chorionic villus sampling (CVS) procedures and 673 amniocenteses]. The indication for an early prenatal test was a high risk for a monogenic disorder in 140 out of the 146 tests performed (143 CVS procedures and three early amniocenteses). In 26 cases, the fetus was found to be affected and early abortion was chosen by the couple in 25 cases (96 per cent). The 670 late prenatal tests were done for various reasons including monogenic disorders (13 per cent), increased risk because of a previous child affected with Down syndrome or a neural tube defect (4.8 per cent), and an increased risk for a chromosomal aberration (78 per cent). In 31 cases of a late prenatal test, the fetus was found to be affected and only 21 couples (70 per cent) opted for an abortion. The major reason for this observation is probably related to religious and cultural factors. Since Arab women do not wish to have prenatal testing for only knowledge or reassurance, these factors should be taken into consideration during pre-amniocentesis counselling.
Prenatal Diagnosis 04/1998; 18(3):219-24. · 2.11 Impact Factor
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J Zlotogora
American Journal of Medical Genetics 02/1998; 75(2):125.
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ABSTRACT: Aspartylglucosaminuria (AGU) is a rare disorder of glycoprotein metabolism caused by the deficiency of the lysosomal enzyme aspartylglucosaminidase (AGA). AGU is inherited as an autosomal recessive trait and occurs with a high frequency in Finland because of a founder effect. While very few patients with AGU have been reported from non-Finnish origin, we diagnosed the disorder in 8 patients originating from 3 unrelated families, all Palestinian Arabs from the region of Jerusalem. The clinical diagnosis of AGU is often difficult, in particular early in the course of the disease, and most of the patients are diagnosed after the age of 5 years. However, since these patients excrete early large amounts of aspartylglucosamine in urine, biochemical screening is easy by urine chromatography.
Journal of Inherited Metabolic Disease 12/1997; 20(6):799-802. · 3.58 Impact Factor
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ABSTRACT: Non-syndromic recessive deafness (NSRD) is the most common form of prelingual hereditary hearing loss. To date, 10 autosomal NSRD loci (DFNBs) have been identified by genetic mapping; at least three times as many additional loci are expected to be identified. We have performed linkage analyses in two inter-related inbred kindreds, comprised of >50 affecteds, from a single Israeli-Arab village segregating NSRD. Genetic mapping by two-point and multi-point linkage analysis in 10 candidate regions identified the segregating gene to be on human chromosome 13q11 (DFNB1). Haplotype analysis, using eight microsatellite markers spanning 15 cM in 13q11, suggested the segregation of two different mutations in this kindred: affected individuals were homozygotes for either haplotype or compound heterozygotes. The gene for the connexin 26 gap junction protein, recently shown to be mutant in both dominant and recessive deafness, maps to this locus. We identified two distinct mutations, W77R and Gdel35, both of which likely inactivate connexin 26. The Gdel35 change likely occurs at a mutational hotspot within the connexin 26 gene. The recombination of marker alleles at the polymorphisms studied in 13q11, at known map distances from the mutations, allowed us to estimate the age of the mutations to be 3-5 generations (75-125 years). This study independently confirms the identity of connexin 26 as an NSRD gene. Importantly, we demonstrate that in small populations with high rates of consanguinity, as compared with large outbred populations, recessive mutations may have very recent origin and show allelic diversity.
Human Molecular Genetics 11/1997; 6(12):2163-72. · 7.64 Impact Factor
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ABSTRACT: We report on eight patients from seven different families affected with a syndrome which includes thumb defects, short stature, microcephaly, and mental retardation. Most of the patients had additional malformations, in particular amenorrhoea and azoospermia in the adults. There were no haematological manifestations and the chromosomes were normal without evidence of breakage even after stimulation. In five of the cases the probands' mother received hormonal treatment before or at the beginning of her pregnancy or both. The syndrome may be inherited as an autosomal recessive trait since the patients included both males and females and their parents were related in most cases. In addition, supporting this possibility, they all originated from a small village which may be considered as an isolate. However, in all cases but one, only one person was affected in each family and there was a significant apparent excess of healthy sibs of the probands. These observations may be the result of the variability of the syndrome or a more complex type of inheritance.
Journal of Medical Genetics 11/1997; 34(10):813-6. · 6.36 Impact Factor
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J Zlotogora
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ABSTRACT: As a consequence of the high consanguinity rate among the Palestinian Arabs, many recessive disorders are present with a relatively high frequency. In a survey of 2000 different Palestinian Arab families who visited our genetic clinic, in 601 an autosomal recessive disease was diagnosed or strongly suspected. The distribution of these disorders was not uniform and some disorders, such as Krabbe disease, were found at high frequency in only a small part of the population. For some other disorders, a high prevalence was also reported among Palestinian Arabs living in other regions, for example, beta thalassaemia, Bardet-Biedl syndrome, Meckel syndrome, autosomal recessive congenital hydrocephalus, and recessive osteopetrosis. In addition, as another consequence of the high consanguinity rate, two different autosomal recessive diseases were diagnosed within the same sibship in 17 of the Palestinian Arab families.
Journal of Medical Genetics 10/1997; 34(9):765-6. · 6.36 Impact Factor
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J Zlotogora
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ABSTRACT: Congenital hydrocephalus and/or open neural tube defect was present in at least one individual of 98 families out of the 2,000 Palestinian Arabic families who have visited the Genetic clinic at the Hadassah Medical Center. In 22 families the brain malformation was part of a syndrome: Meckel syndrome in 10, Warburg syndrome in another 5, Carpenter in one, and undiagnosed in 6 families. In 76 of the families the neural tube defect and/or the hydrocephalus were non-syndromal. It seems that most of the cases of isolated non-syndromal hydrocephalus represented autosomal recessive traits and that an abnormal allele is common among Palestinian Muslim Arabs.
American Journal of Medical Genetics 08/1997; 71(1):33-5.
