Nores et al. (1992) described a case labeled AO type II in which prenatal sonographic and neonatal radiographic findings were correlated to provide the basis of prenatal diagnosis of the entity. Autosomal recessive ... - Prenatal Diagnosis Nores et al. (1992) described a case labeled AO type II in which prenatal sonographic and neonatal radiographic findings were correlated to provide the basis of prenatal diagnosis of the entity. Autosomal recessive inheritance was supported by recurrence in a subsequent pregnancy. The following morphologic features could be recognized by prenatal ultrasonography: coronal clefts of the vertebral bodies, metaphyseal and epiphyseal abnormalities, spinal deviations such as cervical kyphosis and a horizontal sacrum, additional ossification centers in the pelvis, and preaxial deviation of the thumbs and toes.
Sillence et al. (1987) described 4 cases of neonatal death dwarfism resembling atelosteogenesis but with some distinctive radiographic and characteristic histopathologic features. They proposed the name atelosteogenesis II. Atelosteogenesis type II, also called neonatal osseous dysplasia I, is ... Sillence et al. (1987) described 4 cases of neonatal death dwarfism resembling atelosteogenesis but with some distinctive radiographic and characteristic histopathologic features. They proposed the name atelosteogenesis II. Atelosteogenesis type II, also called neonatal osseous dysplasia I, is characterized by severely shortened limbs, small chest, scoliosis, clubfoot of the equinovarus type (talipes equinovarus), abducted thumbs and great toes, and cleft palate. Radiographic findings include cervical kyphosis, scoliosis, and lumbar hyperlordosis with horizontal sacrum, flattened vertebrae with coronal clefts, and round-shaped iliac bones with flat acetabulae. The distal humerus is typically bifid, and the distal femur rounded. The second and/or third metacarpals and first and second metatarsals are often larger than the other bones of the hand and foot. Patients die of respiratory insufficiency shortly after birth because of the collapse of the airways and pulmonary hypoplasia due to the small rib cage. On the basis of reports of parental consanguinity and recurrence among offspring of unaffected parents, AO II is presumed to be inherited as an autosomal recessive trait. AO II is similar to but more severe than the generally nonlethal autosomal recessive chondrodysplasia, diastrophic dysplasia (DTD; 222600) (Sillence et al., 1987; Hastbacka et al., 1996). - De la Chapelle Dysplasia De la Chapelle et al. (1972) described a hitherto unrecognized skeletal dysplasia in a stillborn son and daughter of consanguineous parents. The limbs were strikingly short, with almost triangular fibula and ulna. The middle phalanges were curiously double. Both sibs had cleft palate and patent foramen ovale and ductus Botalli. The boy also had endocrine and hematologic abnormalities. A relationship of this skeletal dysplasia to mesomelic dwarfism of the hypoplastic ulna, fibula and mandible types (249700) could be suggested. Whitley et al. (1986) reported a third affected child (daughter) in the original family and a sporadic case in a male infant born to unrelated parents. Cleft palate was present in all. Respiratory insufficiency was the apparent cause of death in each patient. Cartilage from respiratory structures was abnormal and the abnormality accounts for the consistent triad of laryngeal stenosis, tracheobronchomalacia, and pulmonary hypoplasia. According to Whitley et al. (1986), the possible case of de la Chapelle dysplasia reported by Salonen (1982) has been reclassified as atelosteogenesis type I (108720).
In a Mexican girl with diastrophic dysplasia presenting some unusual clinical and radiographic features that are usually observed in atelosteogenesis type II, Macias-Gomez et al. (2004) identified compound heterozygosity for the R279W (606718.0002) and R178X (606718.0005) mutations in ... In a Mexican girl with diastrophic dysplasia presenting some unusual clinical and radiographic features that are usually observed in atelosteogenesis type II, Macias-Gomez et al. (2004) identified compound heterozygosity for the R279W (606718.0002) and R178X (606718.0005) mutations in the SLC26A2 gene. The patient had cystic swelling of the external ears, cervical kyphosis, rhizomelia, 'hitchhiker' thumbs, bilateral talipes equinovarus, and short toes, features highly suggestive of diastrophic dysplasia. However, she also displayed severe and progressive cervical kyphosis, V-shaped distal humerus, bowed radii, horizontal sacrum, and gap between the first and second toes, features typical of atelosteogenesis type II. Macias-Gomez et al. (2004) concluded that the combination of a mild and a severe mutation led to an intermediate clinical picture, representing an apparent genotype-phenotype correlation.
Because of similarities between atelosteogenesis type II and the much milder, generally nonlethal diastrophic dysplasia, Hastbacka et al. (1995, 1996) studied cultured skin fibroblasts of 3 patients with AOII and found them to have defective sulfate transport and ... Because of similarities between atelosteogenesis type II and the much milder, generally nonlethal diastrophic dysplasia, Hastbacka et al. (1995, 1996) studied cultured skin fibroblasts of 3 patients with AOII and found them to have defective sulfate transport and defective sulfation of proteoglycans as in diastrophic dysplasia. Furthermore, by direct sequencing they observed mutations in all 3 patients in the DTDST gene (see 606718.0002-606718.0004). One of the mutations had also been found in diastrophic dysplasia patients. Thus it is probably no accident that AOII was described by de la Chapelle of Helsinki because diastrophic dysplasia is unusually frequent in Finland. Cases of AOII may be caused by compound heterozygosity for a mutation that causes diastrophic dysplasia when homozygous and another mutation that causes a more severe defect. Rossi et al. (1996) studied fibroblast cultures of 3 patients with mutations in the DTDST gene: one with diastrophic dysplasia (the least severe of the conditions caused by DTDST mutations), one with the more severe atelosteogenesis type II, and one with an intermediate phenotype designated AO2/DTD. Reduced incorporation of inorganic sulfate into macromolecules was found in all 3. Each of the 3 patients was found to be heterozygous for an arg279-to-trp mutation (606718.0002) in the third extracellular loop of the DTDST gene product. In 2 patients (DTD and OA2/DTD), no other structural mutation was found, but PCR amplification and SSCP analysis of fibroblast cDNA showed reduced mRNA levels of the wildtype DTDST allele. Rossi et al. (1996) stated that these 2 patients may be compound heterozygotes for the 'Finnish' mutation which had as yet not been characterized at the DNA level and which was known to cause reduced expression of DTDST. The third patient (with AO2) had the R279W mutation compounded with a novel mutation, the deletion of cytosine-418, predicting a frameshift with premature termination. This allele was underrepresented in the cDNA, in accordance with previous observations that premature stop codons reduce mRNA levels. The presence of the DTDST R297W mutation in a total of 11 patients with AO2 or DTD emphasized the overlap between these conditions. This mutation had not been found in 8 analyzed patients with achondrogenesis type IB (ACG1B), the clinically most severe member of this family of chondrodysplasias, suggesting that the R279W mutation allows some residual activity of the sulfate transporter. In affected members of the patients reported by de la Chapelle et al. (1972), Bonafe et al. (2008) identified a homozygous mutation in the SLC26A2 gene (606718.0013). The findings confirmed that de la Chapelle dysplasia is allelic to other SLC26A2 disorders.
Atelosteogenesis type 2 (AO2) is usually lethal at birth or shortly thereafter because of pulmonary hypoplasia and tracheobronchomalacia. The diagnosis is suspected when the following are present:...
DiagnosisClinical DiagnosisAtelosteogenesis type 2 (AO2) is usually lethal at birth or shortly thereafter because of pulmonary hypoplasia and tracheobronchomalacia. The diagnosis is suspected when the following are present:Clinical featuresRhizomelic limb shortening with normal-sized skullHitchhiker thumbsSmall chestProtuberant abdomenCleft palateDistinctive facial features (midface hypoplasia, depressed nasal bridge, epicanthus, micrognathia)Other usual findings are ulnar deviation of the fingers, gap between the first and second toes, and clubfoot.Radiographic findingsNormal-size skull with disproportionately short skeletonPlatyspondyly, hypodysplastic vertebrae, and cervical kyphosis. Ossification of the upper thoracic vertebrae and coronal clefts of the lumbar and lower thoracic vertebrae may be incomplete.Hypoplastic ilia with flat acetabulum. The pubic bones are often unossified.Shortened long bones with metaphyseal flaring. The distal humerus is sometimes bifid or V-shaped, sometimes pointed and hypoplastic; the femur is distally rounded; the radius and tibia are typically bowed. Note: (1) A distally pointed, triangular humerus had led Slaney et al [1999] to the suggestion of a new condition, but this finding is a typical feature of achondrogenesis 1B (ACG1B) bordering on AO2 [Unger et al 2001]. (2) The first individuals with de la Chapelle dysplasia described by De la Chapelle et al [1972] and Whitley et al [1986] showed a triangular remnant of ulna and fibula. Those individuals were subsequently classified as having AO2 [Bonafé et al 2008].Characteristic hand findings of sulfate transporter-related dysplasia:Hitchhiker thumb with ulnar deviation of the fingers (characteristic of diastrophic dysplasia [DTD])Gap between the first and second toe (characteristic of ACG1B [when the phalanges are identifiable on the x-rays] and DTD)Hypoplasia of the first metacarpal bone (also present in ACG1B and DTD)TestingHistopathologic testing. The histopathology of cartilage is essentially similar to that seen in diastrophic dysplasia (DTD) and achondrogenesis 1B (ACG1B), as it reflects the paucity of sulfated proteoglycans in cartilage matrix [Superti-Furga et al 1996a, Rossi et al 1997]. It shows an abnormal extracellular matrix with threads of fibrillar material between cystic acellular areas and areas of normal cellularity. Some chondrocytes appear surrounded by lamellar material forming concentric rings that are in some cases indistinguishable from the collagen rings typical of ACG1B. The growth plate shows disruption of column formation and hypertrophic zones with irregular invasion of the metaphyseal capillaries and fibrosis. These cartilage matrix abnormalities are present in long bones as well as in tracheal, laryngeal, and peribronchial cartilage, whereas intramembranous ossification shows no abnormalities.Biochemical testing. The incorporation of sulfate in macromolecules can be studied in cultured chondrocytes and/or skin fibroblasts through double labeling with 3H-glycine and 35S-sodium sulfate. After incubation with these compounds and purification, the electrophoretic analysis of medium proteoglycans reveals a lack of sulfate incorporation [Superti-Furga 1994, Rossi et al 1997] which can be observed even in total macromolecules. The determination of sulfate uptake is possible but very cumbersome and is not used for diagnostic purposes [Superti-Furga et al 1996b].Molecular Genetic TestingGene. SLC26A2 (DTDST) is the only gene currently known to be associated with atelosteogenesis type 2 (AO2).Clinical testing. In individuals with radiologic and histologic features compatible with the diagnosis of AO2, mutations in SLC26A2 can be found in more than 90% of alleles [Rossi & Superti-Furga 2001]. Occasionally, in individuals with typical clinical, radiologic, and histologic features of SLC26A2-related dysplasia (even with evidence of defective sulfation in fibroblasts), SLC26A2 molecular testing detects no mutation or only a single heterozygous pathogenic mutation; in these cases, the mutations may be present in the 5' region of the gene:Targeted mutation analysis detects the four most common SLC26A2 mutations (p.Arg279Trp, p.Cys653Ser, p.Arg178X, and c.-26+2T>C ("Finnish" mutation). Of these, p.Arg279Trp, p.Arg178X, and c.-26+2T>C are associated with the AO2 phenotype. Sequence analysis of the SLC26A2 coding region may detect rare "private" mutations in individuals in whom mutation analysis detects none or only one of the common alleles.Table 1. Summary of Molecular Genetic Testing Used in Atelosteogenesis Type 2View in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilitySLC26A2Targeted mutation analysisPanel of four mutations 2~70%ClinicalSequence analysisPrivate and common mutations>95%1. The ability of the test method used to detect a mutation that is present in the indicated gene2. p.Arg279Trp, p.Cys653Ser, p.Arg178X, c.-26+2T>C. Mutation panel may vary by laboratory.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Testing StrategyConfirming/establishing the diagnosis in a probandThe diagnosis is first suspected on the basis of clinical and radiologic findings. Histopathology of cartilage is recommended as second diagnostic step. It is particularly important when radiologic material is not available or is of poor quality.Molecular genetic testing is the preferred diagnostic test in probands with a clinical, radiologic, and/or histopathologic diagnosis of AO2. It allows precise diagnosis in the great majority of cases.Targeted mutation analysis for the four most common mutations is performed first, as it is likely to identify one or both alleles in a significant proportion of probands (one allele in ~40% and both alleles in ~50%).Sequence analysis of the entire coding region is performed when neither or only one allele has been identified by targeted mutation analysis. Parental DNA analysis for the mutations found in the proband is recommended, as most probands are compound heterozygous.Sulfate incorporation assay in cultured skin fibroblasts (or chondrocytes) is possible in the rare cases in which the diagnosis of AO2 is strongly suspected but molecular genetic testing fails to detect SLC26A2 mutations.Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family. Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder.Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.Genetically Related (Allelic) DisordersThree other phenotypes (all with an autosomal recessive mode of inheritance) are associated with mutations in SLC26A2:Achondrogenesis 1B (ACG1B), among the most severe skeletal disorders in humans, is characterized by severe hypodysplasia of the spine, rib cage, and extremities, with a relatively preserved cranium. ACG1B is invariably lethal in the perinatal period [Superti-Furga et al 1996b].Diastrophic dysplasia (DTD) is a skeletal dysplasia characterized by short stature, joint contractures, cleft palate, and characteristic clinical signs such as the "hitchhiker" thumb and cystic swelling of external ears. The first mutations in SLC26A2 were found in individuals with DTD.Recessive multiple epiphyseal dysplasia (EDM4) is characterized by joint pain (usually the hips and knees), malformations of the hands, feet, and knees, and scoliosis. Approximately 50% of individuals have an abnormal finding at birth, e.g., clubfoot, cleft palate, or cystic ear swelling. Median height in adulthood is in the tenth centile [Superti-Furga et al 1996c, Superti-Furga et al 1999, Superti-Furga et al 2001].
Atelosteogenesis type 2 (AO2) is usually lethal in the neonatal period because of lung hypoplasia, tracheobronchomalacia, and laryngeal malformations. Pregnancy complications of polyhydramnios may occur....
Natural HistoryAtelosteogenesis type 2 (AO2) is usually lethal in the neonatal period because of lung hypoplasia, tracheobronchomalacia, and laryngeal malformations. Pregnancy complications of polyhydramnios may occur.AO2 is clinically very similar to diastrophic dysplasia (DTD) [Rossi et al 1996b].Newborns with AO2 present with short limbs, adducted feet with wide space between the hallux and the second toe, hitchhiker thumb, cleft palate, and facial dysmorphism. Disproportion between the short skeleton and normal-sized skull is immediately evident; the limb shortening is mainly rhizomelic; the gap between the toes, ulnar deviation of the fingers, and adducted thumbs are typical of sulfate transporter-related dysplasias [Newbury-Ecob 1998, Superti-Furga et al 2001]. The neck is short, the thorax narrow, and the abdomen protuberant.Cleft palate is a constant feature, whereas the degree of facial dysmorphism is variable. Midface hypoplasia is usually present, together with a flat nasal bridge and micrognathia. Epicanthal folds, ocular hypertelorism, and low-set ears can also be present.Spinal scoliosis and dislocation of the elbows are reported [Newbury-Ecob 1998].
Genotype-phenotype correlations indicate that the amount of residual activity of the sulfate transporter modulates the phenotype [Rossi et al 1997] in a spectrum from lethal ACG1B to mild EDM4. Homozygosity or compound heterozygosity for mutations predicting stop codons or structural mutations in transmembrane domains of the sulfate transporter are associated with the more severe phenotype of ACG1B. The combination of a severe mutation (predicting stop codons or structural mutations in transmembrane domains) with a mutation located in extracellular loops, in the cytoplasmic tail of the protein, or in the regulatory 5'-flanking region of the gene results in the less severe phenotypes, i.e., AO2 and DTD [Hästbacka et al 1996, Superti-Furga et al 1996c, Rossi et al 1997, Karniski 2001, Rossi & Superti-Furga 2001, Karniski 2004]....
Genotype-Phenotype CorrelationsGenotype-phenotype correlations indicate that the amount of residual activity of the sulfate transporter modulates the phenotype [Rossi et al 1997] in a spectrum from lethal ACG1B to mild EDM4. Homozygosity or compound heterozygosity for mutations predicting stop codons or structural mutations in transmembrane domains of the sulfate transporter are associated with the more severe phenotype of ACG1B. The combination of a severe mutation (predicting stop codons or structural mutations in transmembrane domains) with a mutation located in extracellular loops, in the cytoplasmic tail of the protein, or in the regulatory 5'-flanking region of the gene results in the less severe phenotypes, i.e., AO2 and DTD [Hästbacka et al 1996, Superti-Furga et al 1996c, Rossi et al 1997, Karniski 2001, Rossi & Superti-Furga 2001, Karniski 2004].The most common SLC26A2 mutation outside Finland, p.Arg279Trp, is a mild mutation resulting in the EDM4 phenotype when homozygous and mostly in the DTD phenotype when in the compound heterozygous state. In individuals with AO2, the p.Arg279Trp mutation is combined with a severe, structural mutation (e.g., p.Arg178X, p.Leu131Cysfs*41 [Rossi et al 1996b], p.Asn425Asp [Rossi et al 1997], p.Thr512Lys, or c.1751delA). The same mutations associated in some individuals with the AO2 phenotype can be found in individuals with DTD if the second allele is a relatively mild mutation, or in individuals with ACG1B if the second mutation is a structural, severe one [Rossi & Superti-Furga 2001].The mutation p.Cys653Ser is the second-most common, with a frequency among SLC26A2 pathogenic alleles very close to that of mutation c.-26+2T>C in non-Finnish populations. It results in EDM4/rMED when homozygous and in EDM4/rMED or DTD when compounded with other mutations. It is not found in AO2.Mutation p.Arg178X is the third-most common mutation and is associated with the severe phenotypes ACG1B and AO2.c.-26+2T>C, the fourth-most common mutation, is very frequent in Finland ("Finnish" mutation). It produces low levels of correctly spliced mRNA and results in DTD when homozygous.Another mutation specific to the Finnish population is p.Thr512Lys, which results in AO2 (de la Chapelle dysplasia) when homozygous and in DTD when in compound heterozygosity with a milder allele [Bonafé et al 2008].Most other mutations are rare.The same mutations associated in some individuals who have the ACG1B phenotype can be found in individuals with a milder phenotype (EDM4 and DTD) if the second allele is a relatively mild mutation. Indeed, missense mutations located outside the transmembrane domain of the sulfate transporter are often associated with a residual activity that can "rescue" the effect of a null allele [Rossi & Superti-Furga 2001].
Atelosteogenesis type 2 (AO2), rather than diastrophic dysplasia (DTD), must be considered when distinct hypoplasia of one or more long bones (humerus, ulna, radius, or fibula) is present. Histopathology is very similar in the two conditions, although the cartilage growth plate shows fewer disorganized hypertrophic and proliferative zones and columnar zones in DTD than in AO2....
Differential DiagnosisAtelosteogenesis type 2 (AO2), rather than diastrophic dysplasia (DTD), must be considered when distinct hypoplasia of one or more long bones (humerus, ulna, radius, or fibula) is present. Histopathology is very similar in the two conditions, although the cartilage growth plate shows fewer disorganized hypertrophic and proliferative zones and columnar zones in DTD than in AO2.The differentiation of AO2 from other subtypes of atelosteogenesis ("incomplete bone formation"), and even from other lethal skeletal dysplasias, should be based on clinical examination as well as radiographic imaging.The radiologic differentiation of AO2 from the achondrogenesis syndromes (including ACG1B) is based on the more severe underossification of the skeleton and extreme limb shortening seen in ACG1B. Histopathology, which is similar in AO2 and ACG1B because of their common pathogenesis, is helpful in distinguishing between AO1 and AO2.Compared to AO2, atelosteogenesis type 1 shows better development of the long bones and better ossification of the spine and pelvis. Hitchhiker thumb and gap between the toes are not present in AO1 and cleft palate is rare. Absence of the fibula may suggest AO1, whereas dysplasia of the fibula is more typical of AO2. The humerus may be completely absent in AO1.Other disorders in the differential diagnosis with AO2 are the lethal short-rib polydactyly syndromes (when polydactyly is absent) and thanatophoric dysplasia, in which the typical "telephone receiver" femur is visible on x-ray. In thanatophoric dysplasia type II, cloverleaf skull is common.Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the extent of disease in an individual diagnosed with atelosteogenesis type 2 (AO2), the following evaluations are recommended:...
ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with atelosteogenesis type 2 (AO2), the following evaluations are recommended:Complete skeletal surveyRespiratory statusTreatment of ManifestationsProvide palliative care for the viable newborn.Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.Therapies Under InvestigationSearch ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions. Note: There may not be clinical trials for this disorder.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Atelosteogenesis Type 2: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDSLC26A25q32Sulfate transporterFinnish Disease DatabaseSLC26A2Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Atelosteogenesis Type 2 (View All in OMIM) View in own window 256050ATELOSTEOGENESIS, TYPE II; AOII 606718SOLUTE CARRIER FAMILY 26 (SULFATE TRANSPORTER), MEMBER 2; SLC26A2Molecular Genetic PathogenesisMutations in SLC26A2 (DTDST) [Dawson & Markovich 2005] are responsible for the family of chondrodysplasias including achondrogenesis 1B (ACG1B), diastrophic dysplasia (DTD), atelosteogenesis type 2 (AO2), and recessive multiple epiphyseal dysplasia (EDM4) (see Genetically Related Disorders) [Hästbacka et al 1996, Superti-Furga et al 1996a, Rossi et al 1997, Superti-Furga et al 1999, Superti-Furga 2001, Superti-Furga et al 2001]. Impaired activity of the sulfate transporter in chondrocytes and fibroblasts results in the synthesis of proteoglycans, which are either not sulfated or insufficiently sulfated [Rossi et al 1998, Satoh et al 1998], most probably because of intracellular sulfate depletion [Rossi et al 1996a]. Undersulfation of proteoglycans affects the composition of the extracellular matrix and leads to impairment of proteoglycan deposition, which is necessary for proper enchondral bone formation [Corsi et al 2001, Forlino et al 2005]. A correlation exists between the mutation, the predicted residual activity of the sulfate transporter, and the predicted severity of the phenotype [Rossi et al 1997, Cai et al 1998, Rossi & Superti-Furga 2001, Karniski 2004, Maeda et al 2006].Normal allelic variants. The coding sequence of SLC26A2 is organized in two exons separated by an intron of approximately 1.8 kb, and encodes a protein of 739 amino acids that is predicted to have 12 transmembrane domains and a carboxy-terminal, cytoplasmic, moderately hydrophobic domain [Hästbacka et al 1994]. A further untranslated exon is located 5' relative to the two coding exons; it has probable regulatory functions, as the mutation c.-26+2T>C (the "Finnish" allele) located in this region was shown to lead to reduced mRNA transcription [Hästbacka et al 1999].The p.Thr689Ser allele has been frequently observed at the heterozygous or homozygous state in several controls of different ethnicities and is thus a common polymorphism [Cai et al 1998, Rossi & Superti-Furga 2001].There is evidence that p.Arg492Trp is a rare polymorphism, found in seven out of 200 Finnish controls and in five out of 150 non-Finnish controls; in vitro expression of this variant showed normal sulfate transport activity [Bonafé et al 2008]. This allele was erroneously considered pathogenic in previous reports [Rossi & Superti-Furga 2001]. See Table 2.Pathologic allelic variants. Four pathologic alleles of SLC26A2 appear to be recurrent: p.Arg279Trp, p.Cys653Ser, p.Arg178X, and c.-26+2T>C. Together they represent approximately 70% of the pathologic mutations in SLC26A2. See Table 2.Of the four, the p.Arg279Trp, p.Arg178X, and c.-26+2T>C mutations are associated with the AO2 phenotype [Superti-Furga et al 1996c, Rossi & Superti-Furga 2001]. In compound heterozygotes, the phenotype associated with each pathologic allele depends on the combination with the second mutation. Table 2. Selected SLC26A2 Allelic Variants View in own windowClass of Variant AlleleDNA Nucleotide Change (Alias 1)Protein Amino Acid ChangeReference SequencesNormalc.835C>Tp.Arg492TrpNM_000112.3 NP_000103.2c.2065A>Tp.Thr689SerPathologicc.-26+2T>C (IVS1+2T>C)--c.391delC (delC418)p.Leu131Cysfs*41c.532C>Tp.Arg178Xc.835C>Tp.Arg279Trpc.1535C>Ap.Thr512Lysc.1273A>Gp.Asn425Aspc.1957T>Ap.Cys653SerSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org).1. Variant designation that does not conform to current naming conventionsNormal gene product. The sulfate transporter gene SLC26A2 encodes a transmembrane protein that transports sulfate into chondrocytes to maintain adequate sulfation of proteoglycans. The sulfate transporter protein belongs to the family of sulfate permeases. The overall structure with 12 membrane-spanning domains is shared with two other human anion exchangers: (1) PDS, a chloride-iodide transporter involved in Pendred syndrome and (2) CLD, which is responsible for congenital chloride diarrhea. The function of the carboxy-terminal hydrophobic domain of SLC26A2 is not yet known. SLC26A2 is expressed in developing cartilage in human fetuses but also in a wide variety of other tissues [Haila et al 2001]. The size of the predominant mRNA species is greater than 8 kb, indicating the existence of significant untranslated sequences [Hästbacka et al 1994, Hästbacka et al 1999].Abnormal gene product. Most SLC26A2 mutations either predict a truncated polypeptide chain or change amino acids that are located in transmembrane domains or are conserved in man, mouse, and rat. Individuals homozygous for the "Finnish" mutation c.-26+2T>C have reduced levels of mRNA with intact coding sequence [Rossi et al 1996b]. Thus, the mutation presumably interferes with splicing and/or further mRNA processing and transport [Hästbacka et al 1994, Hästbacka et al 1999]. The other Finnish mutation specifically found in individuals with Finnish AO2 (de la Chapelle dysplasia) and DTD, p.Thr512Lys, has been proven to abolish the sulfate transporter activity in vitro [Bonafé et al 2008].The p.Arg178X mutation was shown to abolish sulfate transporter activity in a Xenopus oocyte model [Karniski 2001] and in a HEK-293 cell-culture model [Karniski 2004], respectively.