Diastrophic Dysplasia Sulfate Transporter Gene Research Articles

Diastrophic Dysplasia : A Case Report

Abstract not availableBangladesh J Child Health 2015; VOL 39 (1) :46-49

Dysplastic spondylolysis is caused by mutations in the diastrophic dysplasia sulfate transporter gene

Spondylolysis is a fracture in part of the vertebra with a reported prevalence of about 3-6% in the general population. Genetic etiology of this disorder remains unknown. The present study was aimed at identifying genomic mutations in patients with dysplastic spondylolysis as well as the potential pathogenesis of the abnormalities. Whole-exome sequencing and functional analysis were performed for patients with spondylolysis. We identified a novel heterozygous mutation (c.2286A > T; p.D673V) in the sulfate transporter gene SLC26A2 in five affected subjects of a Chinese family. Two additional mutations (e.g., c.1922A > G; p.H641R and g.18654T > C in the intron 1) in the gene were identified by screening a cohort of 30 unrelated patients with the disease. In situ hybridization analysis showed that SLC26A2 is abundantly expressed in the lumbosacral spine of the mouse embryo at day 14.5. Sulfate uptake activities in CHO cells transfected with mutant SLC26A2 were dramatically reduced compared with the wild type, confirming the pathogenicity of the two missense mutations. Further analysis of the gene-disease network revealed a convergent pathogenic network for the development of lumbosacral spine. To our knowledge, our findings provide the first identification of autosomal dominant SLC26A2 mutations in patients with dysplastic spondylolysis, suggesting a new clinical entity in the pathogenesis of chondrodysplasia involving lumbosacral spine. The analysis of the gene-disease network may shed new light on the study of patients with dysplastic spondylolysis and spondylolisthesis as well as high-risk individuals who are asymptomatic.

Bilateral Double-Layered Patella: MRI Findings and Fusion with Multiple Headless Screws: A Case Report.

The double-layered patella (DLP) was first described by Buttner in 19251. It is a rare entity that is often associated with an autosomal recessive form of multiple epiphyseal dysplasia (MED) caused by a homozygous diastrophic dysplasia sulfate transporter (DTDST) gene mutation2-5, although COMP6 and COL9A27 deletions have also been reported to cause DLP. DLP is a relatively mild form of MED, and clinical findings are often limited to bilateral recurrent anterior knee pain and early-onset hip osteoarthritis (C653S homozygous DTDST gene)2 as well as mild brachydactyly and clubfoot deformity (R279W homozygous DTDST gene)8. If the soft-tissue interface between the anterior and posterior osseous layers in DLP is stable and allows for little motion, patients may be asymptomatic. In these cases, DLP is often discovered incidentally as part of a broader diagnostic evaluation for MED9. However, if the soft-tissue interface is unstable, considerable motion can occur between the two ossified layers, which can cause symptoms, particularly during knee extension. This can present as a sensation of locking, giving way, or subluxation2, or alternatively as painful clicking or a snapping sensation with flexion near 30° to 40° 10,11. There is very limited information regarding the surgical treatment of symptomatic DLP. In several prior reports, a good clinical outcome was achieved with debridement of the soft-tissue interface and fusion of the osseous layers with screws10-12. In a patient with DLP who had undergone unsuccessful soft-tissue stabilization (Ali-Krogius procedure13), Hinrichs et al. utilized a tibial tuberosity medialization addition to a second soft-tissue stabilization2. We present a case of symptomatic bilateral DLP in an adolescent who was treated with fusion with use of four headless screws. The patient’s parents were …

Genotype–phenotype correlation in DTDST dysplasias: Atelosteogenesis type II and diastrophic dysplasia variant in one family

Mutations in diastrophic dysplasia sulfate transporter (DTDST) cause a spectrum of autosomal recessive chondrodysplasias. In decreasing order of severity, they include processes designated as achondrogenesis type IB (ACG-1B), atelosteogenesis type II (AO2), diastrophic dysplasia (DTD), diastrophic dysplasia variant (DTDv), and recessively inherited multiple epiphyseal dysplasia (rMED). This is the first report of an extended family with unequivocally distinct phenotypes on the DTDST spectrum. Two siblings have DTDv and their first cousin had AO2. They all share the common Finnish mutation (IVS1 + 2C>T). The two patients with DTDv have the previously reported R279W extracellular domain missense mutation. The second mutation in the patient with AO2 is c.172delA, a deletion of one nucleotide causing a previously unreported frameshift mutation. This is the first published case of an individual with a frameshift mutation combined with the Finnish mutation. These three patients provide an opportunity, in concert with a review of previous literature, to further examine the genotype-phenotype correlation of DTDST. Analysis suggests that, while the DTDST family of disorders contains at least seven different conditions, mutations in the DTDST gene, in fact, appear to cause a phenotypic continuum. Furthermore, DTDST genotype alone is an imperfect predictor of clinical severity along this continuum.

A variant of Desbuquois dysplasia characterized by advanced carpal bone age, short metacarpals, and elongated phalanges: Report of seven cases

We present the clinical and radiological findings of seven patients with a seemingly new variant of Desbuquois dysplasia (DBQD) and emphasize the radiographic findings in the hand. All cases showed remarkably accelerated carpal bone ages in childhood, but none of the patients had an accessory ossification center distal to the second metacarpal, or thumb anomalies, instead, there was shortness of one or all metacarpals, with elongated appearance of phalanges, resulting in nearly equal length of the second to fifth fingers. The two sibs followed for 20 years showed narrowing and fusion of the intercarpal joints with age and ultimately, precocious degenerative arthritis. The changes in the feet were similar to those of the hands, with advanced tarsal bone ages, shortness of the metatarsals and elongation of the second and third toes. Other radiographic findings were narrowness of the intervertebral disc spaces resulting in precocious degenerative spondylosis and progressive scoliosis. The femoral neck was short and thick and showed a persistent enlargement of the lesser trochanter with a high-riding, bulbous greater trochanter that became more prominent with age. Molecular testing of the diastrophic dysplasia sulfate transporter (DTDST) gene was performed on six patients and no mutations were detected. This radiographic and clinical observation further adds to the evidence that there may be subtypes of DBQD. Long-term follow-up showed that severe precocious osteoarthritis of the hand and spine is a major manifestation of this specific variant.

Prenatal Sonographic Features of Fetal Atelosteogenesis Type 1

A telosteogenesis is a lethal chondrodysplastic disorder characterized by severe micromelia and spinal abnormalities, including a heterogeneous group of disorders with overlapping phenotypic features. 1,2 Three subtypes have been A described on the basis of radiologic and pathologic findings. Type 1 has pathologically unique giant cell chondrodysplasia. Type 2 has similar humeral and femoral bone shapes but typically has a hitchhiker thumb or toe and distinctive chondro-osseous histopathologic features caused by the diastrophic dysplasia sulfate transporter gene, whereas types 1 and 2 are caused by the filamin B gene. Type 3 has less dysmorphic facial features and well-ossified but disharmonious short tubular bones. Atelosteogenesis type 1, a synonym for spondylohumerofemoral hypoplasia, is a rare chondrodysplastic disorder caused by mutations in filamin B located at 3p14. 3,4 This gene has an important role in vertebral segmentation, joint formation, and endochondral ossification. It is characterized by severe rhizomelia with bowing of the limbs, especially the humeri, femurs, proximal and middle phalanges, and fibulas, with distal tapering and delay in ossification of vertebrae. 1,5 Other clinical hallmarks of the disorder include midface hypoplasia, micrognathia with a cleft palate, and a narrow thorax, leading to pulmonary hypoplasia and laryngeal stenosis, attributable to the lethality. 1,5,6 Histopathologic findings are hypocellular and acellular areas and occasional giant cells in the resting cartilage, similar to boomerang dysplasia. 1,5,7 Because atelosteogenesis type 1 is usually lethal, prenatal diagnosis is desirable for proper management. To our best knowledge, only 4 cases have been prenatally diagnosed and reported in the literature. 6,8-10 Here we present the prenatal sonographic features of atelosteogenesis to add to the number of cases, which may be helpful in diagnosis when skeletal dysplasia is encountered.

Dysplastic Histogenesis of Cartilage Growth Plate by Alteration of Sulphation Pathway: A Transgenic Model

Mutations in the diastrophic dysplasia sulphate transporter (dtdst) gene causes different forms of chondrodysplasia in the human. The generation of a knock-in mouse strain with a mutation in dtdst gene provides the basis to study developmental dynamics in the epiphyseal growth plate and long bone growth after impairment of the sulphate pathway. Our microscopical and histochemical data demonstrate that dtdst gene impairment deeply affects tissue organization, matrix structure, and cell differentiation in the epiphyseal growth plate. In mutant animals, the height of the growth plate was significantly reduced, according to a concomitant decrease in cell density and proliferation. Although the pathway of chondrocyte differentiation seemed complete, alteration in cell morphology compared to normal counterparts was detected. In the extracellular matrix, it we observed a dramatic decrease in sulphated proteoglycans, alterations in the organization of type II and type X collagen fibers, and premature onset of mineralization. These data confirm the crucial role of sulphate pathway in proteoglycan biochemistry and suggest that a disarrangement of the extracellular matrix may be responsible for the development of dtdts cartilage dysplasia. Moreover, we corroborated the concept that proteoglycans not only are structural components of the cartilage architecture, but also play a dynamic role in the regulation of chondrocyte growth and differentiation.

A phenotype intermediate between Desbuquois dysplasia and diastrophic dysplasia secondary to mutations in DTDST

We describe a child whose original clinical and radiologic manifestations led to a diagnosis of Desbuquois dysplasia. Subsequent development of features including cervical kyphosis and cystic ears caused us to reconsider the original diagnosis. The new complement of features in this patient fell in a range between Desbuquois dysplasia and diastrophic dysplasia. Molecular testing showed that she is a compound heterozygote for mutations in the diastrophic dysplasia sulfate transporter gene (DTDST). This finding confirms that there is locus heterogeneity in apparent Desbuquois dysplasia. It also expands the phenotypic spectrum of disorders caused by mutations in DTDST.

Fetal MR imaging of atelosteogenesis type II (AO-II)

The diastrophic dysplasia family of osteochondrodysplasias comprises a spectrum of skeletal diseases characterized by abnormal growth and remodelling of cartilage and bone. They are caused by mutations in the diastrophic dysplasia sulfate transporter (DTDST) gene. Different defects in this gene product give rise to the variety of phenotypes based on the level of residual transport capacity. We reported a case of a fetus with this spectrum, evaluated and diagnosed with fetal MRI.

Isolation, characterization and molecular screening of canine SLC26A2 (sulphate transporter) in German Shepherd dogs with hip dysplasia

The SLC26A2 gene codes for a sulphate transporter (the gene is also known as diastrophic dysplasia sulphate transporter gene; DTDST) and is a causative gene for human diastophic dysplasia due to undersulphation of proteoglycans in the cartilage matrix (Hastbacka et al. 1994). Several mutations in the SLC26A2 gene have been found in human diastrophic dysplasia (Hastbacka et al. 1994, 1996), achondrogenesis type IB (Superti-Furga 1994), and multiple epiphyseal dysplasia (Superti-Furga et al. 1999; Czarny-Ratajczak et al. 2001). Over 30 mutations in the SLC26A2 gene have been identified in human to date, including heterozygous single base deletions and splicing site mutations (Hastbacka et al. 1994, 1996; Superti-Furga et al. 1996, 1999; CzarnyRatajczak et al. 2001; Rossi and Superti-Furga 2001). Canine hip dysplasia is a developmental orthopedic disease in which an abnormal formation of the hip leads to looseness in the hip joints, causing cartilage damage (LaFond et al. 2002). Progressive arthritis can result, and when it does, it can be crippling. Hip dysplasia is not the same thing as arthritis in the hips, rather it is the most common cause of arthritis in the hips. Hip dysplasia is most common among larger breeds of dogs, especially German Shepherds, Rottweilers, Labrador Retrievers, Golden Retrievers, Mastiffs and Saint Bernards (Guilliard 2003). It is also seen in smaller breeds such as Cocker Spaniels and Springer Spaniels, as well as in mixed breeds (Guilliard 2003) Hip dysplasia is known to be transmitted genetically (Todhunter and Lust 2003), and recent genetic studies have found major genes for hip dysplasia in four Finnish dog populations (Maki et al. 2004), as well as quantitative trait loci (QTL) contributing to hip dysplasia in PortugueseWater Dogs (Chase et al. 2004). Further, the recent QTL mapping

A compound heterozygote harboring novel and recurrent DTDST mutations with intermediate phenotype between atelosteogenesis type II and diastrophic dysplasia

Diastrophic dysplasia sulfate transporter (DTDST) is a sulfate transporter required for the synthesis of sulfated proteoglycans in the cartilage. Over 30 mutations have been described in the DTDST gene, which result in a continuous clinical spectrum of recessively inherited chondrodysplasias, including, in order of increasing severity, a recessive form of multiple epiphyseal dysplasia (rMED), diastrophic dysplasia (DTD), atelosteogenesis type II (AO-II) and achondrogenesis 1B (ACG-1B). Correlation between disease severity and residual sulfate transport activity has been reported. Here we report a patient with DTDST mutations, whose manifestations fell in a range between AO-II and DTD. The patient was a compound heterozygote for the recurrent c.835C>T (p.R279W) and novel c.1987G>A (p.G663R) mutations. Immunocytochemical analysis in HEK293 cells showed that the p.G663R mutation was localized within the cytoplasm, and not to the cell membrane, suggesting p.G663R is a loss-of-function mutation. Our case supports the previously described correlation between the severity of the phenotype and the putative level of residual transport function.

Functional expression and cellular distribution of diastrophic dysplasia sulfate transporter (DTDST) gene mutations in HEK cells.

Defects in sulfate transport in chondrocytes lead to undersulfation of the cartilage extracellular matrix proteoglycans. Mutations in the diastrophic dysplasia sulfate transporter (DTDST) gene have been linked to four chondrodysplasias of varying severity. To characterize disease-causing mutations of DTDST, we expressed DTDST-mediated sulfate transport in mammalian HEK-293 cells and determined that the wild-type protein is glycosylated and localized to the cell plasma membrane. Four mutations, A715V, C653S, Q454P and R279W, stimulated sulfate transport at rates only 39-62% of wild-type DTDST. These four mutations were expressed on the plasma membrane of the cell, but the amount of expressed protein was reduced when compared with wild-type DTDST. The Q454P mutant is unique in that it is not properly glycosylated in HEK cells. There was no difference in sulfate transport activity between cells transfected with either the DeltaV340 or the G678V mutations and control HEK cells. Furthermore, the G678V mutation is not expressed along the plasma membrane, but is trapped within the cytoplasm. When comparing the sulfate transport capacity of each DTDST mutation with the chondrodysplasia in which it has been identified, we find that individuals with severe achondrogenesis 1B phenotype have null mutations on both DTDST alleles. Heterozygotes for both a null mutation and a partial-function mutation result in either atelosteogenesis type 2 or DTD, whereas the milder, recessive multiple epiphyseal dysplasia phenotype is homozygous for partial-function mutations. In contrast to previous studies in Xenopus laevis oocytes, we find a strong correlation between the severity of the phenotype and the level of residual transport function in mammalian cells.

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.

Achondrogenesis Type IB Agenesis of Cartilage Interterritorial Matrix as the Link Between Gene Defect and Pathological Skeletal Phenotype

Achondrogenesis type IB is a lethal osteochondrodysplasia caused by mutations in the diastrophic dysplasia sulfate transporter gene. How these mutations lead to the skeletal phenotype is not known. Histology of plastic-embedded skeletal fetal achondrogenesis type IB samples suggested that interterritorial epiphyseal cartilage matrix was selectively missing. Cartilage was organized in chondrons separated by cleft spaces; chondrocyte seriation, longitudinal septa, and, in turn, mineralized cartilaginous septa were absent. Agenesis of interterritorial matrix as the key histologic change was confirmed by immunohistology using specific markers of territorial and interterritorial matrix. Biglycan-enriched territorial matrix was preserved; decorin-enriched interterritorial areas were absent, although immunostaining was observed within chondrocytes. Thus, in achondrogenesis type IB: (1) a complex derangement in cartilage matrix assembly lies downstream of the deficient sulfate transporter activity; (2) the severely impaired decorin deposition participates in the changes in matrix organization with lack of development of normal interterritorial matrix; and (3) this change determines the lack of the necessary structural substrate for proper endochondral bone formation and explains the severe skeletal phenotype.

Mutations in the region encoding the von Willebrand factor A domain of matrilin-3 are associated with multiple epiphyseal dysplasia.

Multiple epiphyseal dysplasia (MED) is a relatively mild and clinically variable osteochondrodysplasia, primarily characterized by delayed and irregular ossification of the epiphyses and early-onset osteoarthritis. Mutations in the genes encoding cartilage oligomeric matrix protein (COMP) and type IX collagen (COL9A2 and COL9A3) have previously been shown to cause different forms of MED (refs. 4-13). These dominant forms of MED (EDM1-3) are caused by mutations in the genes encoding structural proteins of the cartilage extracellular matrix (ECM); these proteins interact with high affinity in vitro. A recessive form of MED (EDM4) has also been reported; it is caused by a mutation in the diastrophic dysplasia sulfate transporter gene (SLC26A). A genomewide screen of family with autosomal-dominant MED not linked to the EDM1-3 genes provides significant genetic evidence for a MED locus on the short arm of chromosome 2 (2p24-p23), and a search for candidate genes identified MATN3 (ref. 18), encoding matrilin-3, within the critical region. Matrilin-3 is an oligomeric protein that is present in the cartilage ECM. We have identified two different missense mutations in the exon encoding the von Willebrand factor A (vWFA) domain of matrilin-3 in two unrelated families with MED (EDM5). These are the first mutations to be identified in any of the genes encoding the matrilin family of proteins and confirm a role for matrilin-3 in the development and homeostasis of cartilage and bone.

Mutations in the diastrophic dysplasia sulfate transporter (DTDST) gene: correlation between sulfate transport activity and chondrodysplasia phenotype

The diastrophic dysplasia sulfate transporter (DTDST) gene encodes a transmembrane protein that transports sulfate into chondrocytes to maintain adequate sulfation of proteoglycans. Mutations in this gene are responsible for four recessively inherited chondrodysplasias that include diastrophic dysplasia, multiple epiphyseal dysplasia, atelosteogenesis type 2 and achondrogenesis 1B (ACG-1B). To determine whether the DTDST mutations found in individuals with these chondrodysplasias differ functionally from each other, we compared the sulfate transport activity of 11 reported DTDST mutations. Five mutations, G255E, Delta a1751, L483P, R178X and N425D, had minimal sulfate transport function following expression in Xenopus laevis oocytes. Two mutations, Delta V340 and R279W, transported sulfate at rates of 17 and 32%, respectively, of wild-type DTDST. Four mutations, A715V, C653S, Q454P and G678V, had rates of sulfate transport nearly equal to that of wild-type DTDST. Transport kinetics were not different among the four mutations with near-normal sulfate transport function and wild-type DTDST. When the sulfate transport function of the different DTDST mutations are grouped according to the general phenotypes, individuals with the most severe form, ACG-1B, tend to be homozygous for null mutations, individuals with the moderately severe atelosteogenesis type 2 have at least one allele with a loss-of-function mutation, and individuals with the mildest forms are typically homozygous for mutations with residual sulfate transport function. However, in the X.laevis oocyte expression system, the correlation between residual transport function and the severity of phenotype was not absolute, suggesting that factors in addition to the intrinsic sulfate transport properties of the DTDST protein may influence the phenotype in individuals with DTDST mutations.

Mutations in the diastrophic dysplasia sulfate transporter (DTDST) gene (SLC26A2): 22 novel mutations, mutation review, associated skeletal phenotypes, and diagnostic relevance

Mutations in the diastrophic dysplasia sulfate transporter (DTDST) gene (SLC26A2): 22 novel mutations, mutation review, associated skeletal phenotypes, and diagnostic relevance

Mutations in the diastrophic dysplasia sulfate transporter (DTDST) gene (SLC26A2): 22 novel mutations, mutation review, associated skeletal phenotypes, and diagnostic relevance.

Mutations in the DTDST gene can result in a family of skeletal dysplasia conditions which comprise two lethal disorders, achondrogenesis type 1B (ACG1B) and atelosteogenesis type 2 (AO2); and two non-lethal disorders, diastrophic dysplasia (DTD) and recessive multiple epiphyseal dysplasia (rMED). The gene product is a sulfate-chloride exchanger of the cell membrane. Inactivation of the sulfate exchanger leads to intracellular sulfate depletion and to the synthesis of undersulfated proteoglycans in susceptible cells such as chondrocytes and fibroblasts. Genotype-phenotype correlations are recognizable, with mutations predicting a truncated protein or a non-conservative amino acid substitution in a transmembrane domain giving the severe phenotypes, and non-transmembrane amino acid substitutions and splice site mutations giving the milder phenotypes. The clinical phenotype is modulated strictly by the degree of residual activity. Over 30 mutations have been observed, including 22 novel mutations reported here. The most frequent mutation, 862C>T (R279W), is a mild mutation giving the rMED phenotype when homozygous and mostly DTD when compounded; occurrence at a CpG dinucleotide and its panethnic distribution suggest independent recurrence. Mutation IVS1+2T>C is the second most common mutation, but is very frequent in Finland. It produces low levels of correctly spliced mRNA, and results in DTD when homozygous. Two other mutations, 1045-1047delGTT (V340del) and 558C>T (R178X), are associated with severe phenotypes and have been observed in multiple patients. Most other mutations are rare. Heterozygotes are clinically unaffected. When clinical samples are screened for radiologic and histologic features compatible with the ACG1B/AO2/DTD/rMED spectrum prior to analysis, the mutation detection rate is high (over 90% of alleles), and appropriate genetic counseling can be given. The sulfate uptake or sulfate incorporation assays in cultured fibroblasts have largely been replaced by mutation analysis, but may still be useful in cases where mutation analysis is not informative. Although supplementation of patients' cultured cells with thiols may bypass the transporter defect and enhance sulfation of proteoglycans, therapeutic approaches are not yet available. Mouse models for this and other disorders of sulfate metabolism are being developed to help in developing therapeutic treatments.

Mutations in the diastrophic dysplasia sulfate transporter (DTDST) gene (SLC26A2): 22 novel mutations, mutation review, associated skeletal phenotypes, and diagnostic relevance

(Article was originally published in Human Mutation 17:159–171, 2001) 1. Figure 2 reports a deletion 933 del T. This should be corrected to 933-934 del CT (compare with Table 1, where mutation is reported correctly). 2. Both Table 1 and Figure 2 report a mutation 430C>A (Q135R). This should be corrected to 430C>A (Q135K), as lysine, not arginine, is the codon resulting from the mutation.

Localization of the Netherton Syndrome Gene to Chromosome 5q32, by Linkage Analysis and Homozygosity Mapping

Netherton syndrome (NS [MIM 256500]) is a rare and severe autosomal recessive disorder characterized by congenital ichthyosis, a specific hair-shaft defect (trichorrhexis invaginata), and atopic manifestations. Infants with this syndrome often fail to thrive; life-threatening complications result in high postnatal mortality. We report the assignment of the NS gene to chromosome 5q32, by linkage analysis and homozygosity mapping in 20 families affected with NS. Significant evidence for linkage (maximum multipoint LOD score 10.11) between markers D5S2017 and D5S413 was obtained, with no evidence for locus heterogeneity. Analysis of critical recombinants mapped the NS locus between markers D5S463 and D5S2013, within an <3.5-cM genetic interval. The NS locus is telomeric to the cytokine gene cluster in 5q31. The five known genes encoding casein kinase Ialpha, the alpha subunit of retinal rod cGMP phosphodiesterase, the regulator of mitotic-spindle assembly, adrenergic receptor beta2, and the diastrophic dysplasia sulfate-transporter gene, as well as the 38 expressed-sequence tags mapped within the critical region, are not obvious candidates. Our study is the first step toward the positional cloning of the NS gene. This finding promises a better understanding of the molecular mechanisms that control epidermal differentiation and immunity.