Mutation in WNT10A is associated with an autosomal recessive ectodermal dysplasia: the odonto-onycho-dermal dysplasia

Odonto-onycho-dermal dysplasia is a rare autosomal recessive syndrome in which the presenting phenotype is dry hair, severe hypodontia, smooth tongue with marked reduction of fungiform and filiform papillae, onychodysplasia, keratoderma and hyperhidrosis of palms and soles, and hyperkeratosis of the skin. We studied three consanguineous Lebanese Muslim Shiite families that included six individuals affected with odonto-onycho-dermal dysplasia. Using a homozygosity-mapping strategy, we assigned the disease locus to an ~9-cM region at chromosome 2q35-q36.2, located between markers rs16853834 and D2S353, with a maximum multipoint LOD score of 5.7. Screening of candidate genes in this region led us to identify the same c.697G-->T (p.Glu233X) homozygous nonsense mutation in exon 3 of the WNT10A gene in all patients. At the protein level, the mutation is predicted to result in a premature truncated protein of 232 aa instead of 417 aa. This is the first report to our knowledge of a human phenotype resulting from a mutation in WNT10A, and it is the first demonstration of an ectodermal dysplasia caused by an altered WNT signaling pathway, expanding the list of WNT-related diseases.     

A new autosomal recessive form of Stickler syndrome is caused by a mutation in the COL9A1 gene

Stickler syndrome is characterized by ophthalmic, articular, orofacial, and auditory manifestations. It has an autosomal dominant inheritance pattern and is caused by mutations in COL2A1, COL11A1, and COL11A2. We describe a family of Moroccan origin that consists of four children with Stickler syndrome, six unaffected children, and two unaffected parents who are distant relatives (fifth degree). All family members were clinically investigated for ear, nose, and throat; ophthalmologic; and radiological abnormalities. Four children showed symptoms characteristic of Stickler syndrome, including moderate-to-severe sensorineural hearing loss, moderate-to-high myopia with vitreoretinopathy, and epiphyseal dysplasia. We considered the COL9A1 gene, located on chromosome 6q13, to be a candidate gene on the basis of the structural association with collagen types II and XI and because of the high expression in the human inner ear indicated by cDNA microarray. Mutation analysis of the coding region of the COL9A1 gene showed a homozygous R295X mutation in the four affected children. The parents and four unaffected children were heterozygous carriers of the R295X mutation. Two unaffected children were homozygous for the wild-type allele. None of the family members except the homozygous R295X carriers had any signs of Stickler syndrome. Therefore, COL9A1 is the fourth identified gene that can cause Stickler syndrome. In contrast to the three previously reported Stickler syndrome-causing genes, this gene causes a form of Stickler syndrome with an autosomal recessive inheritance pattern. This finding will have a major impact on the genetic counseling of patients with Stickler syndrome and on the understanding of the pathophysiology of collagens. Mutation analysis of this gene is recommended in patients with Stickler syndrome with possible autosomal recessive inheritance.     

A mutation in COL9A1 causes multiple epiphyseal dysplasia: further evidence for locus heterogeneity

Multiple epiphyseal dysplasia (MED) is an autosomal dominantly inherited chondrodysplasia. It is clinically highly heterogeneous, partially because of its complex genetic background. Mutations in four genes, COL9A2, COL9A3, COMP, and MATR3, all coding for cartilage extracellular matrix components (i.e., the alpha2 and alpha 3 chains of collagen IX, cartilage oligomeric matrix protein, and matrilin-3), have been identified in this disease so far, but no mutations have yet been reported in the third collagen IX gene, COL9A1, which codes for the alpha1(IX) chain. MED with apparently recessive inheritance has been reported in some families. A homozygous R279W mutation was recently found in the diastrophic dysplasia sulfate transporter gene, DTDST, in a patient with MED who had a club foot and double-layered patella. The series consisted of 41 probands with MED, 16 of whom were familial and on 4 of whom linkage analyses were performed. Recombination was observed between COL9A1, COL9A2, COL9A3, and COMP and the MED phenotype in two of the families, and between COL9A2, COL9A3, and COMP and the phenotype in the other two families. Screening of COL9A1 for mutations in the two probands from the families in which this gene was not involved in the recombinations failed to identify any disease-causing mutations. The remaining 37 probands were screened for mutations in all three collagen IX genes and in the COMP gene. The probands with talipes deformities or multipartite patella were also screened for the R279W mutation in DTDST. The analysis resulted in identification of three mutations in COMP and one in COL9A1, but none in the other two collagen IX genes. Two of the probands with a multipartite patella had the homozygous DTDST mutation. The results show that mutations in COL9A1 can cause MED, but they also suggest that mutations in COL9A1, COL9A2, COL9A3, COMP, and DTDST are not the major causes of MED and that there exists at least one additional locus.     

A severe autosomal recessive acromesomelic dysplasia,the Hunter-Thompson type,and comparison with the Grebe type

Summary Two siblings with a short-limb dwarfing condition which we call acromesomelic dysplasia, Hunter-Thompson type are reported. Abnormalities are limited to the limbs and limb joints in this severe form of dwarfism. The middle and distal segments of the limbs are most affected. The lower limbs are more affected than the upper. We are aware of one previously published case of this entity reported by A. G. W. Hunter and M. W. Thompson in 1976. Dislocations of the elbows and ankles were present in all three patients and dislocations of the hips and knees in two. One of the siblings who did not have hip and knee dislocations clinically resembled Grebe chondrodysplasia, another severe acromesomelic dwarfing condition. However, radiological analysis suggests that while acromesomelic dysplasia, Hunter-Thompson type and Grebe chondrodysplasia are related, they are not identical. Grebe chondrodysplasia has been established as an autosomal recessive trait. It appears probable that the entity we describe has the same mode of genetic transmission.     

A homozygous mutation in a novel zinc-finger protein, ERIS, is responsible for Wolfram syndrome 2

A single missense mutation was identified in a novel, highly conserved zinc-finger gene, ZCD2, in three consanguineous families of Jordanian descent with Wolfram syndrome (WFS). It had been shown that these families did not have mutations in the WFS1 gene (WFS1) but were mapped to the WFS2 locus at 4q22-25. A G-->C transversion at nucleotide 109 predicts an amino acid change from glutamic acid to glutamine (E37Q). Although the amino acid is conserved and the mutation is nonsynonymous, the pathogenesis for the disorder is because the mutation also causes aberrant splicing. The mutation was found to disrupt messenger RNA splicing by eliminating exon 2, and it results in the introduction of a premature stop codon. Mutations in WFS1 have also been found to cause low-frequency nonsyndromic hearing loss, progressive hearing loss, and isolated optic atrophy associated with hearing loss. Screening of 377 probands with hearing loss did not identify mutations in the WFS2 gene. The WFS1-encoded protein, Wolframin, is known to localize to the endoplasmic reticulum and plays a role in calcium homeostasis. The ZCD2-encoded protein, ERIS (endoplasmic reticulum intermembrane small protein), is also shown to localize to the endoplasmic reticulum but does not interact directly with Wolframin. Lymphoblastoid cells from affected individuals show a significantly greater rise in intracellular calcium when stimulated with thapsigargin, compared with controls, although no difference was observed in resting concentrations of intracellular calcium.     

Novel compound heterozygous mutations in SLC5A2 are responsible for autosomal recessive renal glucosuria

Familial renal glucosuria is an inherited renal tubular disorder. A homozygous nonsense mutation in the SLC5A2 gene, encoding the sodium/glucose co-transporter SGLT2, has recently been identified in an affected child of consanguineous parents. We now report novel compound heterozygous mutations in the son of non-consanguineous parents. One allele has a p.Q167fsX186 mutation, which is expected to produce a truncated protein, and the other a p.N654S mutation involving a highly conserved residue. These findings confirm that mutations in the SLC5A2 gene are responsible for recessive renal glucosuria.     

COL9A2 and COL9A3 mutations in canine autosomal recessive oculoskeletal dysplasia

Oculoskeletal dysplasia segregates as an autosomal recessive trait in the Labrador retriever and Samoyed canine breeds, in which the causative loci have been termed drd1 and drd2, respectively. Affected dogs exhibit short-limbed dwarfism and severe ocular defects. The disease phenotype resembles human hereditary arthro-ophthalmopathies such as Stickler and Marshall syndromes, although these disorders are usually dominant. Linkage studies mapped drd1 to canine chromosome 24 and drd2 to canine chromosome 15. Positional candidate gene analysis then led to the identification of a 1-base insertional mutation in exon 1 of COL9A3 that cosegregates with drd1 and a 1,267-bp deletion mutation in the 5′ end of COL9A2 that cosegregates with drd2. Both mutations affect the COL3 domain of the respective gene. Northern analysis showed that RNA expression of the respective genes was reduced in affected retinas. These models offer potential for studies such as protein-protein interactions between different members of the collagen gene family, regulation and expression of these genes in retina and cartilage, and even opportunities for gene therapy.     

A mutation in the lipase H (LIPH) gene underlie autosomal recessive hypotrichosis

Hereditary hypotrichosis is a rare autosomal recessive disorder characterized by sparse hair on scalp and rest of the body of affected individuals. Two forms of such hypotrichosis LAH and AH have been mapped on chromosome 18q12.1 and 3q27, respectively. Mutations in desmogelin 4 (DSG4) gene have been reported to underlie LAH. Recently, a deletion mutation in Lipase H (LIPH) gene, located at AH locus, has been identified in two ethnic groups of Russian population. In the present study, a four generation Pakistani family with AH phenotype has been mapped to chromosome 3q27. Sequence analysis of candidate gene LIPH revealed a novel five base pair deletion mutation (c.346–350delATATA) in exon 2 of the gene leading to frameshift and downstream premature termination codon. The mutation reported in the family, presented here, is the second mutation identified in LIPH gene. The identification of a genetic defect in LIPH suggests that this enzyme regulates hair growth.     

Kinky coat, a new autosomal recessive mutation in the musk shrew, Suncus murinus.

A kinky-coat mutant was discovered at the fifth generation of the BAN strain originating from wild musk shrews (Suncus murinus) in Bangladesh. Mating experiments indicated that the kinky-coat character is controlled by a single autosomal recessive gene designated kc (kinky coat), which is not allelic to the gene ch (curly hair) previously reported in the Tr strain derived from wild musk shrews on Taramajima Island, Japan. Because the kc/kc homozygotes were fully fertile and viable, the kc gene should be useful as a genetic marker in linkage studies. In external appearance, homozygotes were characterized by curly vibrissae, somewhat unkept coat hair, and wavy long hair on the tail. Both the length and width of coat hair did not differ significantly between homozygous and normal shrews. Light microscopic observations showed that shafts of the kc coat hair are wavy and often have small swellings with disorganization of the medullary structure. Scanning electron microscopic examinations further revealed that the shafts of the vibrissae, coat hair, and tail hair have abnormalities such as longitudinal fissures, twists, and hollows. It is clear that these modifications caused waviness or curling of the shafts of the three kinds of hairs observed.     

A missense mutation in the LIM2 gene is associated with autosomal recessive presenile cataract in an inbred Iraqi Jewish family

In an inbred Iraqi Jewish family, we have studied three siblings with presenile cataract first noticed between the ages of 20 and 51 years and segregating in an autosomal recessive mode. Using microsatellite repeat markers in close proximity to 25 genes and loci previously associated with congenital cataracts in humans and mice, we identified five markers on chromosome 19q that cosegregated with the disease. Sequencing of LIM2, one of two candidate genes in this region, revealed a homozygous T-->G change resulting in a phenylalanine-to-valine substitution at position 105 of the protein. To our knowledge, this constitutes the first report, in humans, of cataract formation associated with a mutation in LIM2. Studies of late-onset single-gene cataracts may provide insight into the pathogenesis of the more common age-related cataracts.     

Factors responsible for multiple discharge of motoneurons in the facial nucleus in cats

The multiple discharge evoked by stimulation of the caudal trigeminal nucleus in motoneurons of the cat facial nucleus was investigated by an intracellular recording method in acute experiments on cats. The multiple discharge was shown to arise on the basis of gradual depolarization of the motoneuron membranes produced as a result of effective summation of high-frequency excitatory influences arriving from the caudal trigeminal nucleus. Factors facilitating the development of this process are the dendritic localization of synaptic endings of projection neurons of the caudal trigeminal nucleus, the dendritic origin of delayed depolarization processes, and the high input resistance of the motoneuron membrane in the facial nerve nucleus.L. A. Orbeli Institute of Physiology, Academy of Sciences of the Armenian SSR, Erevan. Translated from Neirofiziologiya, Vol. 13, No. 5, pp. 520–530, September–October, 1981.     

A small tandem duplication is responsible for the unstable white-ivory mutation in Drosophila

The white-ivory (wi) mutation, an unstable allele of the white locus in Drosophila, reverts to wild-type at frequencies of 5 X 10(-5) in homozygous females, and 5 X 10(-6) in males and deletion heterozygous females. We show by molecular cloning and Southern blot analysis of DNA from wi flies that a 2.9 kilobase tandem duplication within the white locus is responsible for the mutation. Phenotypic reversion appears, in most cases, to be due to an exact excision of the extra copy of the sequence. Two derivative alleles of wi, one phenotypically wild-type, the other a partial revertant, carry insertions of moderately repetitive DNA from outside the locus, in addition to suffering deletions of some white locus DNA. Earlier genetic data preclude unequal crossing-over between homologs as an explanation for the precise reversions. Rather, an intrachromosomal meiotic event seems to be responsible. Our results suggest that intrachromosomal recombination may be responsible in other systems for a larger number of rearrangements than has been suspected, and that interallelic recombination frequencies in Drosophila do not always correlate in a simple way with DNA length or extent of homology.     

A deletion of the paracellin-1 gene is responsible for renal tubular dysplasia in cattle

Various hereditary diseases analogous to particular human heritable diseases have been identified in cattle. Investigation of these cattle diseases will provide useful information regarding the pathogenesis of the corresponding human diseases. Renal tubular dysplasia is an autosomal recessive disease of Japanese black cattle characterized by renal failure and growth retardation. We have previously mapped the locus responsible for the disease within a region on bovine chromosome 1. In the present study, we further typed additional markers in this region and found that a genomic segment of bovine chromosome 1 including the microsatellite marker BMS4009 was deleted in the affected animals. Construction of a physical map covering this region with BAC clones and comparison of the nucleotide sequences of this region between normal and affected animals revealed that a region of 37 kb including exons 1 to 4 of the bovine paracellin-1 gene was deleted in the affected animals. The paracellin-1 gene, which is the causative gene for human renal hypomagnesemia with hypercaciuria and nephrocalcinosis, encodes a tight junction protein of renal epithelial cells. Therefore, we concluded that deletion of the paracellin-1 gene is responsible for renal tubular dysplasia of cattle, and the cattle disease could be a good model for the human disease.     

Identification of novel pro-alpha2(IX) collagen gene mutations in two families with distinctive oligo-epiphyseal forms of multiple epiphyseal dysplasia.

Multiple epiphyseal dysplasia (MED) is a genetically heterogeneous disorder with marked clinical and radiographic variability. Traditionally, the mild "Ribbing" and severe "Fairbank" types have been used to define a broad phenotypic spectrum. Mutations in the gene encoding cartilage oligomeric-matrix protein have been shown to result in several types of MED, whereas mutations in the gene encoding the alpha2 chain of type IX collagen (COL9A2) have so far been found only in two families with the Fairbank type of MED. Type IX collagen is a heterotrimer of pro-alpha chains derived from three distinct genes-COL9A1, COL9A2, and COL9A3. In this article, we describe two families with distinctive oligo-epiphyseal forms of MED, which are heterozygous for different mutations in the COL9A2 exon 3/intron 3 splice-donor site. Both of these mutations result in the skipping of exon 3 from COL9A2 mRNA, but the position of the mutation in the splice-donor site determines the stability of the mRNA produced from the mutant COL9A2 allele.     

Whole-exome sequencing in a single proband reveals a mutation in the CHST8 gene in autosomal recessive peeling skin syndrome

Generalized peeling skin syndrome (PSS) is an autosomal recessive genodermatosis characterized by lifelong, continuous shedding of the upper epidermis. Using whole-genome homozygozity mapping and whole-exome sequencing, we identified a novel homozygous missense mutation (c.229C>T, R77W) within the CHST8 gene, in a large consanguineous family with non-inflammatory PSS type A. CHST8 encodes a Golgi transmembrane N-acetylgalactosamine-4-O-sulfotransferase (GalNAc4-ST1), which we show by immunofluorescence staining to be expressed throughout normal epidermis. A colorimetric assay for total sulfated glycosaminoglycan (GAG) quantification, comparing human keratinocytes (CCD1106 KERTr) expressing wild type and mutant recombinant GalNAc4-ST1, revealed decreased levels of total sulfated GAGs in cells expressing mutant GalNAc4-ST1, suggesting loss of function. Western blotting revealed lower expression levels of mutant recombinant GalNAc4-ST1 compared to wild type, suggesting that accelerated degradation may result in loss of function, leading to PSS type A. This is the first report describing a mutation as the cause of PSS type A.