Simple Autosomal Recessive Inheritance Research Articles

The genetic basis of clinically-suspected achromatopsia in the United Arab Emirates.

Achromatopsia (ACHM) is a genetically heterogenous relatively stationary congenital autosomal recessive cone disorder characterized typically by photophobia, low vision, nystagmus, hyperopia, grossly normal retinal appearance, and absent photopic responses by full-field electroretinography. Incomplete forms occur as well. This study investigates the genetic basis of clinically-suspected ACHM in the United Arab Emirates. Retrospective case series (January 2016-December 2023) of patients with (1) clinically-suspected ACHM and (2) mutations in ACHM-associated genes (CNGA3, CNGB3, GNAT2, PDE6C, PDE6H, AT6). Twenty-two clinically-suspected patients (19 probands) were identified. Biallelic disease genes and number of probands were CNGA3 (9), CNGB3 (6), PDE6C (1), GNAT2 (1), RGS9BP (1), and CNNM4 (1). Two probands had their diagnoses revised after genetic testing and phenotypic reassessment to RGS9BP-related bradyopsia and CNNM4-related Jalili syndrome. Three additional cases (making 22 total probands) were identified from ACHM gene mutation review - one each related to PDE6C, to AT6, and to CNGB3 in concert with CNGA3 (triallelic disease). All three presented with macular discoloration, an atypical finding for classic ACHM. CNGA3 was the single most frequent implicated gene. Bradyopsia and Jalili syndrome can resemble incomplete ACHM. Macular discoloration on presentation can occur in PDE6C-related disease, AT6-related disease, and triallelic CNGB3/CNGA3-related disease. The possibility for triallelic disease exists and requires genetic counseling beyond that of simple autosomal recessive inheritance.

Phenotypic characterization of idiopathic epilepsy and epilepsy of unknown cause in Irish Setters.

Canine epileptic seizures are common neurological symptom presenting to veterinary practice. Idiopathic epilepsy (IE) with a suspected genetic background has been reported in several dog breeds. Although it has been reported in the Irish Setter (IS), the phenotypic characteristics have not yet been described. The aim of this study was to characterize the phenotype of IE in this breed and to trace its mode of inheritance. Owners of IS were requested to fill in a questionnaire via the Dutch Irish Setter Club concerning the epileptic seizures in their dogs. The data was assessed retrospectively using descriptive statistics. Forty-eight privately owned IS dogs fulfilling tier I criteria for IE according to the International Veterinary Epilepsy Task Force of both sexes were included in the study. The mean age of seizure onset was 41 months. Five of the dogs included in the study had an onset of seizures >6 years of age. These dogs were classified with epilepsy of unknown cause (EUC). Primary generalized tonic-clonic seizures were the most common type of seizure and were seen in almost all dogs. Cluster seizures were reported in 54% of the studied population. Most owners reported pre- (56%) and post-ictal (97%) signs in their dogs. A pedigree analysis of one subpopulation was performed and traced the lineage of 13 affected IS. A segregation analysis of this population rejected a simple autosomal recessive inheritance pattern. The present study supports the occurrence of IE and EUC in the IS. The results provide clinical insight into epileptic seizures in this breed and may be a starting point for further, including genetic, analysis.

A canine autosomal recessive model of collagen type III glomerulopathy

Collagen type III glomerulopathy (Col3GP) is a rare renal disease characterized by massive glomerular accumulations of collagen type III. The disease occurs in both humans and animals, and has been presumed to be heritable with an autosomal recessive inheritance pattern. The pathogenesis is unknown. We describe herein a condition of canine autosomal recessive Col3GP. This spontaneously occurring canine disease was incidentally diagnosed in six mongrel dogs. We then established and studied a pedigree segregating the disease to confirm the genetic nature and inheritance of canine Col3GP. Twenty-nine percent of offspring (14/48) were affected, strongly supporting a simple autosomal recessive inheritance pattern. Kidney specimens were studied by light microscopy, electron microscopy (EM), immunohistochemistry and in situ hybridization. Characteristic findings of Col3GP previously reported in both humans and animals were demonstrated, including massive glomerular collagen type III deposition, and evidence of local mesangial collagen type III synthesis was found. We propose that canine Col3GP may serve as an animal model of human Col3GP. Our initial studies, using simple segregation analysis, showed that the Col3A1 gene was not involved in the disease. This is the first animal model of Col3GP, and further studies of this phenotype in dogs may have the potential to provide information on the pathogenesis and genetics of the disease in both animals and humans, and may thus contribute to the development of treatment regimes.

Finding the mutation responsible for inherited rickets in Corriedale sheep

Inherited rickets of Corriedale sheep is of simple autosomal recessive inheritance. The gross and histological lesions include segmental thickening of physes, persistence of hypertrophic chondrocytes at sites of endochondral ossification, excessive osteoclastic resorption, microfractures and wide unmineralised osteoid seams lining trabeculae and filling secondary osteons. Initial testing revealed concentrations of 25-hydroxyvitamin D3 were normal, but those of 1,25-dihydroxyvitamin D3 were increased in serum of affected sheep, suggesting a defect in the vitamin D receptor. However, in vitro studies on cultured skin fibroblasts revealed normal binding and function of the vitamin D receptor. A genome-wide association study was conducted using the Illumina OvineSNP50 BeadChip. A homozygous region of 199 consecutive single-nucleotide polymorphism loci was identified in affected sheep, covering a region of 10 megabase pairs on ovine chromosome 6. Of the 91 candidate genes in this region, dentin matrix protein 1 gene (dmp1) was considered the most likely as it is known to play critical roles in osteocyte maturation and mineral metabolism. Sequencing of DNA from carriers showed a nonsense mutation 253T/C in dmp1. This T/C transition introduced a stop codon (R145X) that could truncate C-terminal amino acids. Using PCR restriction fragment length polymorphism for this mutation, genotyping showed that all affected sheep were “TT” genotypes, and phenotypically normal sheep were either “CT” or “CC”. These findings suggest that a mutation in dmp1 is responsible for inherited rickets of Corriedale sheep. A simple diagnostic test is currently being designed to identify carriers with the defective “T” alleles.

Pathology of Inherited Rickets in Corriedale Sheep

A skeletal disease with features of rickets and simple autosomal recessive inheritance has been discovered in Corriedale sheep in New Zealand. The clinical signs resemble rickets in other species and include decreased growth rate, thoracic lordosis and angular limb deformities. Gross lesions include segmental thickening of physes, growth arrest lines, collapse of subchondral bone of the humeral head, thickened cortices and enthesophytes around distal limb joints. Microscopically, there is persistence of hypertrophic chondrocytes at sites of endochondral ossification, inappropriate and excessive osteoclastic resorption, microfractures and wide, unmineralized osteoid seams lining trabeculae and filling secondary osteons. This study confirms that this skeletal disease of Corriedale sheep is a newly discovered form of inherited rickets and suggests that the genetic defect may be different from inherited forms of rickets described to date in man and animals.

Disruption of P2RY5, an orphan G protein–coupled receptor, underlies autosomal recessive woolly hair

The genetic determinants of hair texture in humans are largely unknown. Several human syndromes exist in which woolly hair comprises a part of the phenotype; however, simple autosomal recessive inheritance of isolated woolly hair has only rarely been reported. To identify a gene involved in controlling hair texture, we performed genetic linkage analysis in six families of Pakistani origin with autosomal recessive woolly hair (ARWH; OMIM 278150). All six families showed linkage to chromosome 13q14.2-14.3 (Z = 17.97). In all cases, we discovered pathogenic mutations in P2RY5, which encodes a G protein-coupled receptor and is a nested gene residing within intron 17 of the retinoblastoma 1 (RB1) gene. P2RY5 is expressed in both Henle's and Huxley's layers of the inner root sheath of the hair follicle. Our findings indicate that disruption of P2RY5 underlies ARWH and, more broadly, uncover a new gene involved in determining hair texture in humans.

CNS Hypomyelination in Rat Terrier Dogs with Congenital Goiter and a Mutation in the Thyroid Peroxidase Gene

Arrested physical development and neurologic abnormalities were identified in 3 of 5 Rat Terrier puppies at 9 weeks of age. Bilaterally firm symmetrical masses were palpated in the region of the thyroid glands. Low serum total (T4) and free thyroxine (FT4, by equilibrium dialysis) and markedly elevated thyroid stimulating hormone (TSH) concentrations supported the diagnosis of hypothyroidism. At necropsy, the thyroid gland was grossly enlarged and histologically exhibited severe, diffuse hyperplasia of the follicular epithelium. Gross examination of the central nervous system revealed a myelin deficiency, most evident in the corpus callosum. Regional distribution of hypomyelination was confirmed histologically, affecting the corpus callosum and, to a lesser degree, the corona radiata, the longitudinal fibers of the pons, the pyramids, and the lateral funiculi of the spinal cord. Myelin reduction was paralleled by axon reduction, suggesting that hypomyelination was a consequence of reduced axonal formation. A homozygous nonsense mutation in the thyroid peroxidase gene was identified in the affected puppies. The dam and a clinically normal litter mate were heterozygous for this mutation, confirming simple autosomal recessive inheritance of the disease trait. The same mutation, causing congenital hypothyroidism with a goiter was previously described in the Toy Fox Terrier breed. Given the ongoing practice of introducing the Toy Fox Terrier genetic background into some Rat Terrier breeding programs to obtain a smaller stature and the apparent relative incidence of the disorder in the 2 breeds, it is likely that this mutation crossed into the Rat Terrier breed from Toy Fox Terriers fairly recently.

Epilepsy in Irish Wolfhounds

During the last 15 years, breeders have reported an increase in the proportion of Irish Wolfhounds with seizure disorders. Clinical data and pedigrees from closely related Irish Wolfhounds were collected retrospectively and analyzed. Idiopathic epilepsy was diagnosed, by exclusion of other causes for seizures, in 146 (18.3%) of 796 Irish Wolfhounds from 115 litters. The first seizure occurred by the age of 3 years in 73% of all dogs. Males were more commonly affected than females (61.6% versus 38.4%), with males having a later average age of seizure onset. The life expectancy of affected dogs was decreased by 2 years when compared with the average Irish Wolfhound population. The heritability index for the affected dogs, their littermates, and unaffected parents was 0.87. No simple mode of inheritance explains the pattern of affected dogs in pedigrees. Hallmarks of dominant and sex-linked inheritance were notably absent, and the segregation ratio was less than would be expected for simple autosomal recessive inheritance. Assuming all affected dogs have the same form of epilepsy, the simplest description of the complex pattern of inheritance observed is autosomal recessive, with incomplete penetrance and male dogs at increased risk.

Epilepsy in Irish Wolfhounds

During the last 15 years, breeders have reported an increase in the proportion of Irish Wolfhounds with seizure disorders. Clinical data and pedigrees from closely related Irish Wolfhounds were collected retrospectively and analyzed. Idiopathic epilepsy was diagnosed, by exclusion of other causes for seizures, in 146 (18.3%) of 796 Irish Wolfhounds from 115 litters. The first seizure occurred by the age of 3 years in 73% of all dogs. Males were more commonly affected than females (61.6% versus 38.4%), with males having a later average age of seizure onset. The life expectancy of affected dogs was decreased by 2 years when compared with the average Irish Wolfhound population. The heritability index for the affected dogs, their littermates, and unaffected parents was 0.87. No simple mode of inheritance explains the pattern of affected dogs in pedigrees. Hallmarks of dominant and sex‐linked inheritance were notably absent, and the segregation ratio was less than would be expected for simple autosomal recessive inheritance. Assuming all affected dogs have the same form of epilepsy, the simplest description of the complex pattern of inheritance observed is autosomal recessive, with incomplete penetrance and male dogs at increased risk.

Renal Lipofuscinosis in Danish Slaughter Cattle

A study was performed to characterize dark brown or black discoloured kidneys ("black kidneys") in Danish slaughter cattle and to investigate the aetiology and pathogenesis. In 133 939 cattle entering four abattoirs, 359 cases of "black kidneys" were recorded. Of these, 57 cases were submitted for macroscopical, microscopical, and ultrastructural examination. A pigment with characteristics similar to those of lipofuscin was found in secondary lysosomes in epithelial cells of the proximal tubules. Pigment accumulation was the cause of discoloration, with a positive correlation between the discoloration of the renal cortex and the degree of pigment accumulation. Cases occurred only in cattle of the Holstein breed or the Red Danish Dairy breed and mainly in animals aged 3 years or older. In these breeds, prevalences of 0.44% and 2.51% were found, respectively. Epidemiological analyses indicated that affected animals aged 4.5 to 6.5 years or 7.5 to 8.5 years were culled more frequently than unaffected cattle. Epidemiological and genealogical analyses strongly indicated a genetic aetiology with simple autosomal recessive inheritance.

Collie eye anomaly in the rough collie in Sweden: genetic transmission and influence on offspring vitality.

Between 1989 and 1997, 8204 rough collies were examined for collie eye anomaly (CEA) at up to 10 weeks of age. All dogs were positively identified and the results were registered under the Swedish Kennel Club genetic health programme. A significant decrease in litter size occurred if one of two affected parents had coloboma (3.8 pups) compared with litters from two chorioretinal dysplasia- (CRD-) affected collies (5.2 pups) or litters by two normal collies (5.0 pups), indicating an influence of the coloboma genotype on offspring vitality. The prevalence of CRD in pups from normal x normal matings and CRD x CRD matings was significantly different from that expected under simple autosomal recessive inheritance (43 per cent versus 25 per cent and 85 per cent versus 100 per cent). The results are compatible with polygenic inheritance but not with simple autosomal recessive inheritance. CRD prevalence in offspring of CRD x coloboma matings was significantly lower than in pups of CRD x CRD matings, reflecting effects of the coloboma genotype on vitality. These results have important implications for breeding programmes and the genetic control of CEA.

Haim-Munk syndrome and Papillon-Lefèvre syndrome are allelic mutations in cathepsin C

Of the many palmoplantar keratoderma (PPK) conditions, only Papillon-Lefèvre syndrome (PLS) and Haim-Munk syndrome (HMS) are associated with premature periodontal destruction. Although both PLS and HMS share the cardinal features...

Genetic control of susceptibility to ozone-induced changes in mouse tracheal electrophysiology

Genetic factors influence the responses of humans and rodents to ozone (O3) inhalation. We previously demonstrated differential O3-induced decreases of tracheal potential (VT) in C57BL/6J (B6) and C3H/HeJ (C3) strain mice. To characterize the genetic basis of this strain-specific response, we measured VT in progeny of B6 and C3 strain mice and in six additional inbred strains of mice 6 h after O3 exposures (2 ppm x 3 h). First filial generation (F1) mice and second generation backcrosses with the resistant parent were uniformly resistant. The distribution of VT in second generation backcrosses with the susceptible parent resembled that of a population composed of resistant and susceptible mice in a 1:1 ratio. These data suggested simple autosomal recessive inheritance of susceptibility. However, overlapping distributions prevented statistical confirmation of that hypothesis. Strain screening revealed a susceptible phenotype in 129/J, A/J, B6, C3HeB/FeJ, and SJL/J and a resistant phenotype in AKR/J, C3, and CBA/J inbred mouse strains. Because this pattern of susceptibility to changes in VT differs from that of susceptibility to lung inflammation, the genetic factors that determine these two responses to acute O3 are not identical.

Three new recessive behavior mutants in the domestic pigeon

Descriptions and breeding tests are reported for three new mutants producing uncoordinated behavior in the domestic pigeon, Columba livia. They were discovered by fanciers separately and have been named "erratic," "wobbly," and "crazy." The affected birds can survive and breed in cages, with some difficulty. All have shown simple autosomal recessive inheritance, and at least "erratic" and "crazy" are not alleles. Maintenance of the mutants is generally best from matings of heterozygotes. Gene symbols proposed for the mutants are er, wo, and cy.

Epidemiologic findings in congenital anemia, dyserythropoiesis, and dyskeratosis in polled Hereford calves.

Congenital dyserythropoiesis and dyskeratosis occur within certain lines of Polled Hereford cattle. Eighty-nine of 90 alleles in 45 affected calves had a mechanism in which they could be identical by descent from an identified common ancestor. The line allele may have been a recurrence of the mutation, or the mutation may have occurred earlier in the breed's history and been distributed throughout the breed by the extensive use of several ancestors. No evidence of disease has been identified in sire and dams of affected calves, suggesting that the allele is not acting in a dominant or incompletely dominant manner. Even distribution of cases between sexes suggests that the disease is not sex linked or sex influenced. A higher degree of inbreeding in the affected calves and temporal and spatial features that separated individual cases also suggest a genetic cause. Segregation ratios were not significantly different from those of the hypothesized simple autosomal recessive inheritance.

Progressive retinal atrophy in miniature longhaired dachshund dogs

A form of generalized progressive retinal atrophy unlike other previously recorded canine retinal dystrophies has been investigated in Miniature Longhaired Dachshund dogs. Segregation patterns in litters from matings involving affected individuals were consistent with simple autosomal recessive inheritance. The earliest ophthalmoscopic signs, appearing at approximately 6 months of age and coinciding in some cases with the onset of nyctalopia, included changes in the granular appearance of the tapetal fundus followed by generalized tapetal hyper-reflectivity and retinal vascular attenuation; later there was irregular loss of pigment in the non-tapetal fundus and optic atrophy. However, there was marked variation in the age of onset and progression of the disease, even within a single litter. The electroretinogram was normal in waveform and latency in four affected littermates at 10 weeks of age but by 9 months was markedly reduced in amplitude in two pups and virtually extinguished in the others. Significant histological changes at 10.5 weeks of age included thinning of the outer nuclear layer, irregularity and attenuation of the rod photoreceptor outer segments and early disorganization of the rod outer segment disc lamellae. By 25 weeks the photoreceptors were grossly degenerate with short rounded inner segments and only residual amounts of outer segment material remaining. This condition in the Miniature Longhaired Dachshund is later in onset than rod-cone dysplasia in Irish Setters but significantly earlier than progressive retinal atrophy in Tibetan Terriers and progressive rod-cone degeneration in, for example, Miniature Poodles. The condition could therefore serve as a potentially useful model for retinitis pigmentosa in man.

Defective brush-border expression of intrinsic factor-cobalamin receptor in canine inherited intestinal cobalamin malabsorption

Ligand binding activity of intrinsic factor-cobalamin receptor (IFCR) was determined in homogenates and isolated brush-border membranes (BBM) of ileum and kidney from dogs exhibiting simple autosomal recessive inheritance of selective cobalamin malabsorption (Fyfe, J. C., Giger, U., Hall, C. A., Jezyk, P. F., Klumpp, S. A., Levine, J. S., and Patterson, D. F. (1991) Pediatr. Res. 29, 24-31). IFCR activity of affected dog ileal homogenates was 3-4-fold higher than normal whereas IFCR activity in affected dog kidney homogenates was one-tenth of normal. The recovery of IFCR activity in the BBM of ileum and renal cortex of affected dogs was 30- and 20-fold less than normal, respectively. The dissociation constant (Kd) for intrinsic factor-cobalamin was similar in BBM of both tissues and was the same in affected and normal dogs. In the affected dog ileal BBM, activities of alkaline phosphatase and sucrase-isomaltase and vesicular transport of glucose and Na(+)-taurocholate were normal. Immunoblots showed no IFCR cross-reactive material in the ileal or renal BBM of affected dogs. IFCR purified by affinity chromatography from kidney of both normal and affected dogs had an Mr = 230,000. However, amino acid analysis revealed that the affected dog IFCR had more lysine than the normal, and protease cleavage of the purified IFCRs revealed different peptide maps. Asparagine-linked oligosaccharides of both proteins were sensitive to peptide N-glycosidase F cleavage, but only the affected dog IFCR was endoglycosidase H sensitive. These results suggest that cobalamin malabsorption in this canine family is caused by inefficient BBM expression of IFCR due to a mutation of IFCR and its retention in an early biosynthetic compartment.

Inherited Selective Intestinal Cobalamin Malabsorption and Cobalamin Deficiency in Dogs

Inherited selective intestinal malabsorption of cobalamin (Cbl) was observed in a family of giant schnauzer dogs. Family studies and breeding experiments demonstrated simple autosomal recessive inheritance of this disease. Affected puppies exhibited chronic inappetence and failure to thrive beginning between 6 and 12 wk of age. Neutropenia with hypersegmentation, anemia with anisocytosis and poikilocytosis, and megaloblastic changes of the bone marrow were present. Serum Cbl concentrations were low, and methylmalonic aciduria and homocysteinemia were present. Parenteral, but not oral, cyanocobalamin administration rapidly eliminated all signs of Cbl deficiency except for low serum Cbl concentrations. Cbl malabsorption in affected dogs was documented by oral administration of [57Co]cyanocobalamin with or without simultaneous oral administration of intrinsic factor or normal dog gastric juice. Quantitation and function studies of intrinsic factor and transcobalamin-II from affected dogs revealed no abnormality. Other gastrointestinal functions and ileal morphology were normal, indicating a selective defect of Cbl absorption at the level of the ileal enterocyte. Immunoelectron microscopy of ileal biopsies showed that the receptor for intrinsic factor-Cbl complex was absent from the apical brush border microvillus pits of affected dogs. This canine disorder resembles inherited selective intestinal Cbl malabsorption (Imerslund-Gräsbeck syndrome) in humans, and is a spontaneously occurring animal model of early onset Cbl deficiency.

Congenital Defects of the Bovine Central Nervous System

Congenital brain defects in cattle are usually obvious at birth, but detection may depend on the nature and extent of the defect. The cause may be genetic or environmental, or the cause may be unknown. Many central nervous system defects are inherited as a simple autosomal recessive trait and may have a significant economic impact on purebred and commercial cattle operations. A common structural defect of genetic nature is internal hydrocephalus. A functional defect of simple autosomal recessive inheritance is bovine progressive degenerative myeloencephalopathy. The most significant teratogenic agents causing central nervous system defects are prenatal viral infections such as bovine virus diarrhea and bluetongue viruses. Many other defects of the central nervous system are reviewed.

Unusual pedigree patterns in seven families with spinal muscular atrophy; further evidence for the allelic model hypothesis.

Clinical and genetic findings are presented in 18 patients, from 7 pedigrees with different types of spinal muscular atrophy (SMA). The SMA diagnosis was based on EMG and muscle biopsy findings. All 7 pedigrees show an unusual genetic pattern, not consistent with simple autosomal recessive inheritance. Furthermore, in 6 of the 7 pedigrees different types of SMA were present within each pedigree. Our findings can be explained by an extension of a multiple alleles hypothesis originally described by Becker in 1964.