A novel <i>SOX9</i> H169Q mutation in a family with overlapping phenotype of mild campomelic dysplasia and small patella syndrome

Matsushita, Masaki; Kitoh, Hiroshi; Kaneko, Hiroshi; Mishima, Kenichi; Kadono, Izumi; Ishiguro, Naoki; Nishimura, Gen

doi:10.1002/ajmg.a.36134

Cited by 29 publications

(25 citation statements)

References 24 publications

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“…The range of functions that Sox proteins serve is broad, including maintaining stem cell features, restricting lineage, and directing terminal differentiation. Germline SOX9 heterozygous inactivating missense and nonsense mutations result in campomelic dysplasia, a syndrome resulting in skeletal malformations, central nervous system dysfunction, as well as abnormalities in other organs [1–2]. …”

Section: Introductionmentioning

confidence: 99%

Recurrent, truncating SOX9 mutations are associated with SOX9 overexpression, KRAS mutation, and TP53 wild type status in colorectal carcinoma

et al. 2016

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PurposeThe extent to which the developmental transcription factor SOX9 functions as an oncogene or tumor suppressor in colorectal carcinoma (CRC) is debatable. We aimed to clarify the effect of SOX9 mutations on SOX9 protein expression and their association with known molecular subtypes and clinical characteristics in advanced CRC.Experimental DesignNext generation sequencing data (MSK-IMPACT) from CRC patients was used to interrogate SOX9, KRAS, NRAS, BRAF, TP53, APC, and PIK3CA. Mutant and wild type (WT) SOX9 cases underwent immunohistochemical (IHC) staining to assess protein expression. SOX9 allele-specific copy number was assessed by Affymetrix Oncoscan array.ResultsSOX9 was mutated in 38 of 353 (10.7%) CRC, of which 82% were frameshift or nonsense. Compared to SOX9 WT, SOX9 mutation was strongly associated with coexistent mutant KRAS (p=0.0001) and WT TP53 (p=0.0004). SOX9 was overexpressed in both SOX9 mutant and WT CRC. Among SOX9 mutants, the highest expression was noted for truncating exon 3 mutants (mean H scores 239±105 versus 147±119, p value=0.02). Further, SOX9 truncating mutants with loss of the WT allele demonstrated protein overexpression indicating the WT protein was not required for protein stabilization.ConclusionsSOX9 is overexpressed in CRC, including those with recurrent distal truncating mutations. The latter has structural similarity to the oncogenic isoform MiniSOX9, which is distally truncated due to aberrant splicing. This information suggests that truncated SOX9 has oncogenic features. SOX9 mutations are highly enriched in KRAS mutant and TP53 wild type CRC; and may provide a therapeutic target in approximately 11% of CRC.

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Section: Introductionmentioning

confidence: 99%

Recurrent, truncating SOX9 mutations are associated with SOX9 overexpression, KRAS mutation, and TP53 wild type status in colorectal carcinoma

et al. 2016

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“…Despite this large number of reported SOX9 mutations in ACD, the functional consequences of these mutations have only occasionally been tested experimentally. For five missense mutations, four in the HMG domain (M113V, R152P, H165Q, and H169Q) and one in the dimerization domain (A76E), residual DNA-binding (Meyer et al 1997) and also transactivation of SOX9 target genes has been demonstrated (Sock et al 2003;Staffler et al 2010;Matsushita et al 2013). Pop et al (2005) studied a cohort of 10 CD cases, including several cases with longer survival and two ACD cases, which were all heterozygous for the nonsense mutation Y440X that truncates the C-terminal transactivation domain spanning residues 402-509 of SOX9.…”

Section: Discussionmentioning

confidence: 99%

A mutation creating an upstream initiation codon in theSOX95′UTRcauses acampomelic campomelic dysplasia

Bohlen

Böhm

Pop

et al. 2017

Molec Gen & Gen Med

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BackgroundCampomelic dysplasia (CD) is a semilethal developmental disorder caused by mutations in and around SOX9. CD is characterized by multiple skeletal malformations including bending (campomelia) of long bones. Surviving patients frequently have the acampomelic form of CD (ACD).MethodsThis is a single case report on a patient with clinical and radiological features of ACD who has no mutation in the SOX9 protein‐coding sequence nor a translocation with breakpoint in the SOX9 regulatory domain. We include functional studies of the novel mutant protein in vitro and in cultured cells.ResultsThe patient was found to have a de novo heterozygous mutation c.‐185G>A in the SOX9 5′UTR. The mutation creates an upstream translation start codon, uAUG, with a much better fit of its flanking sequence to the Kozak consensus than the wild‐type AUG. By in vitro transcription‐translation and transient transfection into COS‐7 cells, we show that the uAUG leads to translation of a short peptide from a reading frame that terminates just after the wild‐type AUG start codon. This results in reduced translation of the wild‐type protein, compatible with the milder phenotype of the patient.ConclusionFindings support the notion that more mildly affected, surviving CD/ACD patients carry mutant SOX9 alleles with residual expression of SOX9 wild‐type protein. Although rarely described in human genetic disease and for the first time here for CD, mutations creating upstream AUG codons may be more common than generally assumed.

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“…Excluding chromosomal rearrangements, to our knowledge nine SOX9 missense mutations [Friedrich et al, 2000;Thong et al, 2000;Moog et al, 2001;Sock et al, 2003;Michel-Calemard et al, 2004;Wada et al, 2009;Staffler et al, 2010;Matsushita et al, 2013] and one insertion causing frameshift [Beaulieu Bergeron et al, 2009] have been detected in patients with acampomelic campomelic dysplasia. The missense mutation c.316A>G (p.Lys106Glu) detected in our patient has not been reported previously as causing acampomelic campomelic dysplasia.…”

Section: To the Editormentioning

confidence: 94%

SOX9 p.Lys106Glu mutation causes acampomelic campomelic dysplasia: Prenatal and postnatal clinical findings

Preikšaitienė

Benušienė

Matulevičienė

et al. 2015

American J of Med Genetics Pt A

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We report on a patient with p.Lys106Glu mutation of SOX9 gene causing acampomelic campomelic dysplasia and present comprehensive prenatal and postnatal clinical findings.A 28-year-old primigravida was referred for a first trimester scan at 14 weeks of amenorrhea. The couple was nonconsanguineous and healthy. She had neither a history of prenatal exposure to teratogenic agents nor any family history of congenital malformations. A prenatal ultrasound showed a live fetus with micrognathia, narrow thorax, bilateral renal pyelectasis (3.5 mm), grade 3 echogenic bowel, bowing of tibia and fibula (angulation of the deformity 31 degrees), and talipes equinovarus (Fig. 1A). The crown-rump length was 80.2 cm, the head circumference was 9.98 cm (37th centile), and the femur and humerus measured 1.51 cm (3rd centile) and 1.8 cm (3rd centile), respectively. Nuchal translucency thickness was 0.9 mm. Amniocentesis at 16 weeks of gestation revealed a normal female karyotype. A follow-up ultrasound at 18 weeks unexpectedly demonstrated straight tibia (Fig. 1B). The head circumference of the fetus was 14.48 cm (4th centile), and the femur and humerus measured 2.61 cm (26th centile) and 2.75 cm (66th centile). A 4D ultrasound examination at 21 weeks of gestation further demonstrated micrognathia and low set ears. Proptosis and microstomia were additionally noted at 28 weeks of gestation.After premature rupture of membranes at 38 weeks of gestation, a Caesarean section was performed. The female infant weighed 2,456 g (3rd centile), and had a head circumference of 32 cm (3rd centile), a length of 48 cm (10th centile), and Apgar scores of 6 after 1 min. and 8 after 5 min. The condition of the newborn was severe due to respiratory distress. Immediate continuous positive airway pressure was used during the first 3 hr after birth, and within the next few days the oxygen was provided via nasal cannula. Hypotonia manifested from birth. The phenotype was remarkable for a flat face, low-set ears, shallow orbits, Pierre Robin sequence, microstomia, short neck, small chest, scoliosis, congenital bilateral metatarsus varus deformities, congenital dislocation of the hips, clitoromegaly, and tracheobronchomalacia. Radiological findings included scoliosis and kyphosis of the thoracic spine, 11 pairs of ribs, abnormal cervical vertebral bodies, dysplasia of thoracic vertebrae, and no overt bending of the long bones (Fig. 1C). Further investigation such as brain and cervical spine MRI, echocardiography, and renal and abdominal ultrasound examination showed no significant abnormalities. For the correction of clubfeet, plaster casts were applied. Dislocation of the hips was treated with the Frejka pillow. The neonatal period was complicated by feeding problems and poor weight gain. Tube feeding could be terminated 1 month after birth. The girl had a few complicated respiratory infections. During the evaluation at the age of 6 months, the head circumference was 42 cm (25th centile), her weight was 4,520 g (<3rd centile), and her length was 60 cm (<3rd ...

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A novel SOX9 H169Q mutation in a family with overlapping phenotype of mild campomelic dysplasia and small patella syndrome

Cited by 29 publications

References 24 publications

Recurrent, truncating SOX9 mutations are associated with SOX9 overexpression, KRAS mutation, and TP53 wild type status in colorectal carcinoma

Recurrent, truncating SOX9 mutations are associated with SOX9 overexpression, KRAS mutation, and TP53 wild type status in colorectal carcinoma

A mutation creating an upstream initiation codon in theSOX95′UTRcauses acampomelic campomelic dysplasia

SOX9 p.Lys106Glu mutation causes acampomelic campomelic dysplasia: Prenatal and postnatal clinical findings

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