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PubMed1999

Autosomal recessive nonsyndromic hearing loss.

Nearly all genes for autosomal recessive nonsyndromal inherited hearing loss (ARNSHL) localized thus far cause prelingual severe to profound or profound hearing impairment. Of the 25 reported loci, most have been identified using single consanguineous families. Six of these genes have been cloned and encode a variety of proteins, including ion channels, extracellular matrix components, cytoskeletal components, and proteins essential for synaptic vesicular trafficking. One of these genes appears to be responsible for approximately 50% of all congenital severe to profound or profound hearing loss in many world populations, and mutations in two other genes can lead to either syndromic or nonsyndromic forms of deafness. The identification of additional genes that cause ARNSHL and elucidation of their function will refine our understanding of auditory physiology at the molecular level.

Deafness↗
PubMed2000

Syndrome of autosomal recessive polycystic kidneys with skeletal and facial anomalies is not linked to the ARPKD gene locus on chromosome 6p.

We report on two sibs, both males, one born at 37 the other at 24 weeks of gestation, both with a syndrome similar to that seen in three sets of sibs by Gillessen-Kaesbach et al. [1993: Am J Med Genet 45:511-518]. Both propositi had polycystic kidneys and hepatic fibrosis indistinguishable from that seen in autosomal recessive polycystic kidney disease (ARPKD), and skeletal and facial anomalies. Skeletal abnormalities included "butterfly" vertebrae, square shape of pelvis, and brachymelia. The facial anomalies included hypertelorism, epicanthic folds, and anteverted nares. Additional external findings were apparently low-set ears and a short neck. Histopathological examination of the kidneys showed radial orientation and cystic dilatation of the cortical and medullar tubules. The liver showed "congenital hepatic fibrosis." The hepatic findings in the second infant were less severe. Renal abnormalities were limited to focal tubular cystic changes. Linkage analysis with polymorphic markers of the region 6p21.1-p12, flanking the gene locus of ARPKD, showed different haplotypes in the sibs, thus excluding the ARPKD gene locus in this family and indicating genetic heterogeneity.

Abortion, Induced↗
PubMed1997

Usher syndrome in the Samaritans: strengths and limitations of using inbred isolated populations to identify genes causing recessive disorders.

We have previously reported significant linkage between markers on 11q13.5 and Usher syndrome type 1 (USH1B) in a large Samaritan kindred. USH1B is an autosomal recessive disease characterized by profound congenital sensorineural deafness, vestibular dysfunction and progressive visual loss. A unique haplotype found only in all USH1B carriers and affected individuals implied that the disease-causing mutation probably entered the community from a single founder. Screening for mutations in a gene called GARP, which was mapped to the same genetic interval as USH1B, revealed a base substitution in the coding region of the gene, in a homozygous state in all affected individuals. This base substitution, which results in an arginine to tryptophane change, is not found in control individuals and occurs at an amino acid residue that is conserved across species, including mouse, gorilla, chimpanzee and macaque. This study emphasizes the strength of using an isolated inbred population for efficient identification of the primary linkage and for narrowing the disease interval, but also demonstrates its limitations in distinguishing between mutations causing the disease and those representing unique and private polymorphisms.

Arginine↗
PubMed1996

Murine autosomal recessive polycystic kidney disease with multiorgan involvement induced by the cpk gene.

BACKGROUND: Autosomal recessive (AR) polycystic kidney disease (PKD) is characterized in humans and mice as a rapidly progressive, collecting duct cystic disease usually leading to uremia in the neonatal or infantile period. In humans, ARPKD renal pathology can be variable in severity and is associated with the development of prominent bile duct and liver pathology. The C57BL/6J-cpk/cpk mouse model of ARPKD is the most extensively studied murine model of inherited infantile PKD; however, these mice lack extrarenal pathology. METHODS: In the present study, the cpk gene was backbreed onto CD1 mice to examine the development of cpk-induced ARPKD in this outbred mouse background. Resulting cystic offspring were examined morphologically and their serum urea nitrogen levels were assessed. RESULTS: The rapid development of PKD in CD1 mice homozygous for the cpk gene appears to be slightly more rapid but otherwise comparable to that seen in inbred C57BL/6J mice. In CD1-cpk/cpk mice, the principal renal pathological finding is collecting duct cysts, which are lined by a relatively uniform epithelium. This epithelium appears to be relatively undifferentiated based on almost total absence of intercalated cells. Proximal tubule cysts are prominent in the first postnatal week while collecting duct cysts predominate in the later stages of the disease. Extrarenal manifestations of the cpk gene are evident in the CD1 strain and include cysts of pancreatic, common bile, and major hepatic ducts. Intrahepatic bile ducts also have focal dilations. Primary (thymus) and secondary (spleen) lymphoid tissues become hypoplastic as azotemia progresses. The strain-related variability in renal and liver changes in cpk-induced ARPKD may reflect the influence of other genes (possibly modifier genes) expressed in this mouse strain. In older CD1-cpk/+ mice, renal (proximal tubular) cysts and prominent liver cysts (lined by a biliary epithelium) develop, indicating that the heterozygous state (cpk/+ genotype) causes renal and hepatic pathology. CONCLUSIONS: The cpk gene, when placed on an appropriate mouse strain background, causes multiorgan disease that more closely mimics human ARPKD than when the cpk gene is expressed on the C57BL/6J strain. A gene dose effect is present as cystic pathology is present in kidney and liver of both suckling homozygous (cpk/cpk) and old heterozygous (cpk/+) mice.

Animals↗
PubMed1998

Lethal neonatal autosomal recessive axonal sensorimotor polyneuropathy.

Peripheral neuropathy is an uncommon cause of generalized hypotonia and weakness in infancy. It occurs as a part of the clinical syndrome in some neurodegenerative disorders of infancy, but seldom causes respiratory failure or swallowing difficulties. We report a lethal autosomal recessive axonal polyneuropathy with neonatal onset in a large kindred from Northern Mississippi. One patient was studied in detail at our medical center and the information on 12 other affected infants in this large family were gathered from medical records and by interviewing the family members. Patients were symptomatic for the polyneuropathy before birth and died in the first year of life from respiratory complications. Thirteen babies were affected by this clinical phenotype in four generations of this family with a high frequency of consanguinity. Affected babies were of both sexes and were born to healthy consanguineous parents. The clinical phenotype of polyneuropathy in our index patient and other affected babies in this family was similar, and represents a unique form of hereditary neonatal polyneuropathy.

Age of Onset↗
PubMed1998

Confirmation of prenatal diagnosis results of X-linked recessive myotubular myopathy by mutational screening, and description of three new mutations in the MTM1 gene.

X-linked recessive myotubular myopathy (XLMTM; MTM1) is a severe neonatal disorder often causing perinatal death of the affected males. The responsible gene, designated MTM1, was localized to proximal Xq28 and recently isolated. The characterization of MTM1 allowed us to screen for causing mutations in three families, previously investigated by linkage analysis. Using exon amplification, single strand conformation polymorphism, and subsequent sequencing analysis, three new mutations and their mutational origin were characterized by analyzing 10 exons. An acceptor splice site and a frameshift mutation were correlated with the concurrent appearance of XLMTM in two families. A third intronic mutation was also analyzed by reverse transcription PCR and revealed a cryptic splice site mutation cosegregating with the presumed XLMTM haplotype in the third family. These results further support the implication of the MTM1 gene in XLMTM and allow efficient and reliable carrier and prenatal diagnosis in these families. Direct mutational diagnosis of families at risk in combination with haplotype analysis avoid the drawbacks using only linkage analysis, make genetic counselling far more reliable, and early clinical management of this disease more appropriate. Moreover, pedigree analyses provide first information on de novo mutation frequency in this newly identified human disease gene.

DNA Mutational Analysis↗
PubMed1998

Identification of mutations in the connexin 26 gene that cause autosomal recessive nonsyndromic hearing loss.

Mutations in the Cx26 gene have been shown to cause autosomal recessive nonsyndromic hearing loss (ARNSHL) at the DFNB1 locus on chromosome 13q12. Using direct sequencing, we screened the Cx26 coding region of affected and nonaffected members from seven ARNSHL families either linked to the DFNB1 locus or in which the ARNSHL phenotype cosegregated with markers from chromosome 13q12. Cx26 mutations were found in six of the seven families and included two previously described mutations (W24X and W77X) and two novel Cx26 mutations: a single base pair deletion of nucleotide 35 resulting in a frameshift and a C-to-T substitution at nucleotide 370 resulting in a premature stop codon (Q124X). We have developed and optimized allele-specific PCR primers for each of the four mutations to rapidly determine carrier and noncarrier status within families. We also have developed a single stranded conformational polymorphism (SSCP) assay which covers the entire Cx26 coding region. This assay can be used to screen individuals with nonsyndromic hearing loss for mutations in the CX26 gene.

Alleles↗
PubMed1999

Three homozygous PTC mutations in the collagen type VII gene of patients affected by recessive dystrophic epidermolysis bullosa: analysis of transcript levels in dermal fibroblasts.

The Hallopeau-Siemens variant of recessive dystrophic epidermolysis bullosa (HS-RDEB) is a severe inherited skin disease characterized by the absence of collagen type VII (COLVII) and anchoring fibrils (AF), caused by mutations in collagen type VII gene (COL7A1). Mutations leading to the formation of premature termination codons (PTCs) of translation are the characteristic genetic lesions in HS-RDEB patients; many PTC mutations have been found to be associated with a marked reduction or complete absence of COLVII mRNA. In this article, we report homozygosity for three different mutations in the COL7A1 of HS-RDEB patients. One mutation, the R2685X, falling in exon 109, is a novel mutation, whereas the other two, the 425A-->G falling in exon 3 and the 497insA in exon 4, have been previously identified in compound heterozygosity with different mutations in other unrelated RDEB patients. Haplotype analysis in three Italian families carrying the 497insA mutation suggested a common origin of this mutation and indicated that this is an ancestral Italian mutation. All these mutations generate PTCs and are associated with the absence of COLVII expression, as detected by immunofluorescence analysis of the patient's skin. Evaluation of the levels of the mutated COLVII mRNAs in cultured skin fibroblasts of the patients and of their parents showed that all the mutated transcripts were expressed at consistent levels. Therefore, our results indicate that a marked mRNA reduction is not a constant feature associated with PTC mutations in COL7A1.

Adolescent↗
PubMed2000

An update of the mutation spectrum of the survival motor neuron gene (SMN1) in autosomal recessive spinal muscular atrophy (SMA).

Spinal muscular atrophy (SMA) is characterized by degeneration of motor neurons in the spinal cord, causing progressive weakness of the limbs and trunk, followed by muscle atrophy. SMA is one of the most frequent autosomal recessive diseases, with a carrier frequency of 1 in 50 and the most common genetic cause of childhood mortality. The phenotype is extremely variable, and patients have been classified in type I-III SMA based on age at onset and clinical course. All three types of SMA are caused by mutations in the survival motor neuron gene (SMN1). There are two almost identical copies, SMN1 and SMN2, present on chromosome 5q13. Only homozygous absence of SMN1 is responsible for SMA, while homozygous absence of SMN2, found in about 5% of controls, has no clinical phenotype. Ninety-six percent of SMA patients display mutations in SMN1, while 4% are unlinked to 5q13. Of the 5q13-linked SMA patients, 96.4% show homozygous absence of SMN1 exons 7 and 8 or exon 7 only, whereas 3. 6% present a compound heterozygosity with a subtle mutation on one chromosome and a deletion/gene conversion on the other chromosome. Among the 23 different subtle mutations described so far, the Y272C missense mutation is the most frequent one, at 20%. Given this uniform mutation spectrum, direct molecular genetic testing is an easy and rapid analysis for most of the SMA patients. Direct testing of heterozygotes, while not trivial, is compromised by the presence of two SMN1 copies per chromosome in about 4% of individuals. The number of SMN2 copies modulates the SMA phenotype. Nevertheless, it should not be used for prediction of severity of the SMA.

Amino Acid Sequence↗
PubMed1997

Bipolar disorder: dominant or recessive on chromosome 5?

The presence of a susceptibility locus for bipolar disorder on chromosome 5p near the dopamine transporter gene has been suggested. We examined 52 bipolar families for linkage to two markers in this region under both dominant and recessive models of inheritance. The purpose of the analyses was to determine the mode of inheritance of this purported bipolar locus. We also ran sensitivity analyses to confirm the reliability of the linkage results. Our results suggest that a bipolar locus inherited in an autosomal dominant fashion may be linked to this region in a subset of families.

Bipolar Disorder↗
PubMed1999

Segregation analysis of the specific response to allergens: a recessive major gene controls the specific IgE response to Timothy grass pollen.

Segregation analysis of the specific response to allergens (SRA) was performed in a sample of 234 randomly selected Australian families using the regressive models. Various SRA phenotypes were considered using broad and narrow definitions of these phenotypes, according to the type of test used, skin test or RAST test, and the specificity of the response to allergen. Strong evidence for familial dependencies among blood relatives was shown for most SRA phenotypes, especially when using a broad definition. There was no evidence for a Mendelian factor accounting for the familial transmission of these broadest phenotypes, which may involve multiple factors preventing the clear detection of a major effect with Mendelian transmission. However, segregation of a Mendelian recessive major gene was detected for one SRA sub-phenotype, the IgE response to a single allergen, Timothy grass pollen, measured by the RAST test. Identification of a specific SRA phenotype controlled by a major gene may have important implications for further linkage studies.

Adolescent↗
PubMed2000

Autosomal recessive multiple pterygium syndrome: a new variant?

Multiple pterygium syndromes include at least 15 different entities characterized by multiple pterygia or webs of the skin and multiple congenital anomalies. We describe a female infant who presented with a distinct constellation of multiple anomalies consisting of pterygia of the inguinal, intercrural and popliteal areas, flexion contractures and arthrogryposis of some joints, craniofacial anomalies including ectropion, medial canthal web, blepharophimosis, hypoplasia of nose, oral and nasopharyngeal cavities, vocal cords and tongue, micrognathia, orolabial synechiae secondary to pterygia, low set ears, alopecia, sad and expressionless face, short neck, asymmetric nipples, anal stenosis, rectal polyp, hypoplastic labia majora, complete syndactyly of all fingers and toes, pes equinovarus, bandlike web between feet, and absence of the nails and phalangeal-palmar creases. Radiological examination showed synostosis, absence or hypoplasia of metacarpal, metatarsal and phalangeal bones on feet and hands, and hypoplasia of pelvic bones and scapulae. This pattern of anomalies does not fit entirely any of the known multiple pterygium syndromes. Autosomal recessive inheritance is most likely due to the presence of three similarly affected siblings and normal parents.

Abnormalities, Multiple↗
PubMed2000

Genetic heterogeneity in Noonan syndrome: evidence for an autosomal recessive form.

Most Noonan syndrome (NS) families are compatible with autosomal dominant inheritance with predominance of maternal transmission. Sporadic patients can be explained by new autosomal dominant mutations. Here we report four Dutch NS patients, two male and two female, each with unaffected consanguineous parents. All four had a typical NS phenotype and presented with hypertrophic obstructive cardiomyopathy (HOCM) at birth. In two cases the HOCM improved, in one case it deteriorated, and in one case it remained constant over 12 years. These patients support the existence of an autosomal recessive form of NS in which HOCM is more frequent than in autosomal dominant NS.

Adolescent↗
PubMed2000

Uruguay facio-cardio-musculo-skeletal syndrome: a novel X-linked recessive disorder.

We report on three male patients from a single family with a brachyturricephaly, "pugilistic" facial appearance, a muffled voice, cardiomyopathy, muscular hypertrophy, broad hands, wide feet with progressive pes cavus deformities, dislocation of toes, variable congenital hip dislocation, and scoliosis. Three other males in the family, now deceased from cardiac disease, appear to have had the same disorder. The mother of the propositus has milder signs of the syndrome. All affected males are related through the maternal line. These cases represent an apparently previously undescribed X-linked recessive syndrome.

Abnormalities, Multiple↗
PubMed2001

New autosomal recessive cerebellar ataxia disorder in a large inbred Lebanese family.

A large inbred Lebanese pedigree with congenital spastic ataxia, microcephaly, optic atrophy, short stature, speech defect, abnormal osmiophilic pattern of skin vessels, cerebellar atrophy, and severe mental retardation transmitted as an autosomal recessive trait has been studied. None of the children had any evidence of a metabolic disease, and the analysis of respiratory chain complex abnormalities was unremarkable. Only one child had a history of perinatal difficulties. Differential diagnosis and the possibility that this disorder is a hitherto unreported one are discussed.

Adolescent↗
PubMed2001

Condition of microcephaly, growth retardation, joint contractures, atopic dermatitis, and mental retardation in two Japanese sisters: a new autosomal recessive MCA/MR syndrome?

We report on two sisters in a family with a hitherto undescribed MCA/MR condition characterized by growth retardation, severe microcephaly, a peculiar facies, congenital contractures of the interphalangeal and patellar joints, atopic dermatitis, and growth and developmental delay. The disorder in the family we describe is similar to but clearly distinguished from tricho-rhino-phalangeal syndromes or Bavinck syndrome. We propose that the condition in the sisters represents a new autosomal recessive MCA/MR syndrome.

Abnormalities, Multiple↗
PubMed2000

A -96C-->T mutation in the promoter of the collagen type VII gene (COL7A1) abolishing transcription in a patient affected by recessive dystrophic epidermolysis bullosa.

Hereditary dystrophic epidermolysis bullosa (DEB) refers to a group of clinically heterogeneous skin blistering diseases due to mutations in the collagen type VII gene (COL7A1). We report two novel mutations found in a patient affected by the most severe form of DEB, the recessive Hallopeau-Siemens variant (HS-RDEB): the R1978X nonsense mutation, in exon 72, and the -96C-->T transition, in the promoter region. The allele specific analysis of the transcripts from skin fibroblasts of the patient showed that the -96C-->T mutation is associated to the absence of collagen type VII (COLVII) mRNA. This mutation, the first one ever identified in the promoter of COL7A1, falls in an Sp1 motif, localized between nucleotides -96 and -91. Gel shift analysis indicated that the -96/-91 sequence is a functional Sp1 site and that the -96C-->T transition inhibits the binding of the trascription factor. These data indicate that the -96/-91 sequence is a crucial Sp1 site whose integrity is necessary for COL7A1 expression. The compound heterozygosity for the -96C-->T null mutation and for the R1978X mutation leads to the absence of COLVII at skin level and to the severe phenotype of the HS-RDEB patient. Hum Mutat 16:275, 2000.

Cells, Cultured↗
PubMed1999

Immunohistochemical and subcellular localization of Parkin protein: absence of protein in autosomal recessive juvenile parkinsonism patients.

Autosomal recessive juvenile parkinsonism (AR-JP) is a distinct clinical entity characterized by a selective degeneration of nigral neurons. Recently, the parkin gene responsible for AR-JP has been identified. Now, we report the subcellular localization of Parkin protein in patients with AR-JP or Parkinson's disease (PD) and in controls by immunoblotting and immunohistochemistry using antibodies raised against the Parkin molecule. Parkin protein was absent in all regions of the brains of patients with AR-JP. Parkin protein was not decreased in the brains of sporadic PD patients. Immunoreactivity was detected in a few Lewy bodies. Parkin protein was located in both the Golgi complex and cytosol.

Brain↗