GENE-39678; No. of pages: 3; 4C: Gene xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Gene journal homepage: www.elsevier.com/locate/gene
A novel deletion mutation involving TMEM38B in a patient with autosomal recessive osteogenesis imperfecta Elisa Rubinato a,⁎, Anna Morgan b, Angela D'Eustacchio b, Vanna Pecile b, Giulia Gortani b, Paolo Gasparini a,b, Flavio Faletra b a b
University of Trieste, Trieste, Italy Institute for Maternal and Child Health, IRCCS “Burlo Garofolo”, Trieste, Italy
a r t i c l e
i n f o
Article history: Received 12 January 2014 Received in revised form 4 May 2014 Accepted 9 May 2014 Available online xxxx Keywords: TMEM38B OI AR SNP array Homozygous deletion
a b s t r a c t Osteogenesis imperfecta (OI) is a hereditary bone disease characterized by decreased bone density and multiple fractures, usually inherited in an autosomal dominant manner. Several gene encoding proteins related to collagen metabolism have been described in some cases of autosomal recessive OI (including CRTAP, LEPRE1, PPIB, FKBP65, SERPINF1, BMP1, WNT1, FKBP10). Recently, TMEM38B, a gene that encodes TRIC-B, a monovalent cation-specific channel involved in calcium flux from intracellular stores and in cell differentiation, has been associated with autosomal recessive OI. Here, we describe the second deletion-mutation involving the TMEM38B gene in an 11 year-old Albanian female with a clinical phenotype of OI, born to parents with suspected consanguinity. SNP array analysis revealed a homozygous region larger than 2 Mb that overlapped with the TMEM38B locus and was characterized by a 35 kb homozygous deletion involving exons 1 and 2 of TMEM38B gene. © 2014 Elsevier B.V. All rights reserved.
1. Introduction Osteogenesis imperfecta (OI) is a hereditary disease characterized by low bone mass with altered bone microarchitecture, leading to increased bone fragility and deformity (Rohrbach and Giunta, 2012). OI is a clinically and genetically heterogeneous disorder, inherited in about 90% of individuals in an autosomal dominant manner. OI etiology is directly or indirectly related to an abnormal synthesis or structure of type I collagen, the most abundant protein of extracellular bone matrix. Type I collagen is a triple helical molecule synthesized as procollagen from COL1A1 and COL1A2, and mutations in these genes are found in the majority of affected individuals (Rohrbach and Giunta, 2012; Marini and Blissett, 2013). However, in the last few years several genes (including CRTAP, LEPRE1, PPIB, FKBP65, SERPINF1, BMP1, WNT1, FKBP10) have been linked to autosomal recessive (AR) forms of OI. Additional, but yet unclassified genes (Marini and Blissett, 2013), including SP7 and TMEM38B, had been associated with AR OI. In particular, a study of multiplex consanguineous families and simplex cases of Saudi Arabian origin revealed that TMEM38B contributes to AR OI in that population (Shaheen et al., 2012). In three families a complete loss of TMEM38B exon 4 (NM_018112.1:c.455_542del) was detected.
Abbreviations: OI, osteogenesis imperfecta; AR, autosomal recessive; PCR, polymerase chain reaction; SNP, single nucleotide polymorphism. ⁎ Corresponding author at: Medical Genetics, Institute for Maternal and Child Health, IRCCS “Burlo Garofolo”, Via dell'Istria 65/1, Trieste, Italy. E-mail address: [email protected] (E. Rubinato).
The same deletion was also described in ten individuals from three independent Israeli Bedouin consanguineous families showing a clinical phenotype compatible with OI type IV (Volodarsky et al., 2013). In all cases a 4.8 Mb region of homozygosity was detected, between marker rs1819743 and marker rs4979370. Within this region the same deletion was demonstrated, suggesting a possible common founder effect. Here we describe a novel AR mutation involving TMEM38B gene, causing a clinical phenotype compatible with OI. 2. Patient and methods 2.1. Clinical report The proband is an 11-year old Albanian girl, born to healthy parents from the same small village, with suspected consanguinity. The parents did not present any limb/spine deformities. She presented with bone fragility, osteopenia and mild conductive hearing loss. The patient had seven fractures at birth, involving both the upper and lower extremities (in particular both femurs, right tibia, right ulna and three ribs). Subsequently in the first seven years of life, eight additional fractures occurred along with generalized demineralization. In particular, femural and tibia fractures required surgical reduction with placements of rods. Given the frequency of fractures and the low mineral density detected (Zscore: − 2.6 sd) the patient underwent several cyclic treatments with bisphosphonate (Neridronate, 2 mg/kg every 90 days). She had a good response in terms of fracture reduction, with no more episodes observed after two years of follow-up, and with increased bone mineral
http://dx.doi.org/10.1016/j.gene.2014.05.028 0378-1119/© 2014 Elsevier B.V. All rights reserved.
Please cite this article as: Rubinato, E., et al., A novel deletion mutation involving TMEM38B in a patient with autosomal recessive osteogenesis imperfecta, Gene (2014), http://dx.doi.org/10.1016/j.gene.2014.05.028
2
E. Rubinato et al. / Gene xxx (2014) xxx–xxx
density (Zscore: − 1.5 sd). Clinically the patient did not have joint hypomobility and she can ambulate independently, without walking aids. Radiographs of lower limbs, lateral spine and skull at 10 years of age, after surgery and bisphosphonate treatment, showed mild demineralization and no bone deformity (Fig. 1). Bilateral mild conductive hearing loss was detected at 10 years old. On visual inspection, she had normal scleral hue, no dysmorphic features and no dentinogenesis imperfecta. The ultrasound examination detected no organ involvement. Echocardiography showed no alterations. Furthermore, her intellectual function was normal. Her height was 140 cm (50° percentile), her weight was 53 kg (95° percentile), without growth deficiency. 2.2. Molecular analysis Molecular analysis of COL1A1 and COL1A2 genes was negative for the presence of causative mutations. Because of the suspected consanguinity between the parents, a SNP array analysis was performed using the Illumina Infinium SNP genotyping platform (HumanOmniExpress — 12 chips and BeadStation Scanner), in order to detect regions of homozygosity encompassing genes known to be involved in recessive forms of OI. Briefly, 200 ng of DNA at a concentration of 50 ng/μL was processed and the genotyping reaction steps were performed according to the manufacturer's specifications. Data analysis was performed using different software such as GenomeStudio 2011.1 (cnv Partition 3.2.0) and PennCNV. Since we demonstrated the presence of homozygous
areas, we used Nexus Copy Number 7.0 software (Biodiscovery, El Segundo, Calif.) to calculate the possible presence of consanguinity. To confirm the deletion and to define the exact breakpoints, a long PCR amplification between the two SNPs was carried out. PCR was performed with KAPA HiFi HotStart ReadyMix (2×), according to manufacturer's protocol (initial step of 5 min at 95 °C, followed by 30 cycles of 20 s at 95 °C, 15 s at 60 °C, and 11 min at 72 °C; Primer Forward-GAGCTGTC ACAATACCTTGTG, Primer Reverse-CACCAATACTATGAACAGGTGA). Then, using internal primers, a 33,891 kb homozygous deletion was characterized (Fig. 1). PCR was performed with KAPA2G Fast HotStart ReadyMix PCR Kit, according to manufacturer's protocol (initial step of 3 min at 96 °C, followed by 30 cycles of 15 s at 96 °C, 15 s at 60 °C, and 1 s at 72 °C; Primer Forward-CACGACCTGTGCTCACTGCA, Primer Reverse-TTGAAACTGACCCACCAGGG). Moreover we studied all the repeat sequences nearby the deletion using a web-tool (http://www. repeatmasker.org) (Tarailo-Graovac and Chen, 2009). 3. Results SNP array analysis revealed several homozygosity regions and among these, only one was larger than 2 Mb (chr9:107,793,426– 109,935,841). This region overlaps with the TMEM38B locus, and was characterized by a 35 kb homozygous deletion spanning from marker rs1567368 to rs9408800 and involving only exons 1 and 2 of TMEM38B gene. To confirm the deletion and to define the exact
Fig. 1. Molecular and radiological findings. A) The area between the (*) represents the largest homozygosity region that overlaps with the TMEM38B locus. The (+) indicates the 35 kb deletion involving exons 1 and 2 of TMEM38B gene. B) Electropherograms of the wild type allele of mother (m) and father (f) and of the mutated allele of mother (m), father (f) and daughter (d). The black arrows show the breakpoints. C) Key radiographs from the proband at 10 years of age (lateral spine, skull and lower limbs).
Please cite this article as: Rubinato, E., et al., A novel deletion mutation involving TMEM38B in a patient with autosomal recessive osteogenesis imperfecta, Gene (2014), http://dx.doi.org/10.1016/j.gene.2014.05.028
E. Rubinato et al. / Gene xxx (2014) xxx–xxx
3
breakpoints, a long PCR amplification between these two SNPs was carried out. Then, using internal primers, a 33,891 kb (chr9: 108.444.592– 108.478.483) deletion was identified (Fig. 1). The deletion was inherited from both parents. To demonstrate the possible presence of consanguinity we checked the overall amount of homozygosity and we found that the total segment homozygosity was almost 19,66 Mb, resulting in a 6th degree of consanguinity (Kearney et al., 2011). Eventually, studying all the repeat sequences near the deletion, we demonstrated the presence of ALU and SINE sequences upstream and of a LINE sequence downstream of the deletion. In particular, we examined 1 kb upstream and 1 kb downstream of the deletion. The ALU/SINE was detected in the position between chr9:108,444,366 and chr9:108,444,664, whereas the LINE/L1 was identified between chr9:108,478,466 and chr9:108,478,878. In both cases the breakpoints were included in the repeat sequences.
Concerning the molecular alteration, we confirmed a 35 kb homozygous deletion involving exons 1 and 2 of TMEM38B gene within a homozygous region larger than 2 Mb that overlapped the TMEM38B gene. Since the deletion was found within a homozygous area, it is very likely that it was due to a common ancestor carrying the mutation. In order to demonstrate it, we used Nexus Copy Number 7.0 software (Biodiscovery, El Segundo, Calif.), and we identified a 6th degree of consanguinity between the parents. Finally, we postulated that the deletion was promoted by the presence of repeat sequences in the segments before and after the breakpoints. In conclusion, our finding expands current knowledge on the role of TMEM38B deletions in causing autosomal recessive OI. Given this novel mutation report and the amount of repeat sequences within and close to this gene, it is possible that additional novel deletions will be discovered in the near future.
4. Discussion
Conflict of interest
In this case report, we identified the second mutation of TMEM38B causing AR OI. TMEM38B encodes an ubiquitously expressed monovalent cation channel protein, TRIC-B (trimeric intracellular cation channel type B), involved in calcium flux from intracellular stores and in cell differentiation (Yamazaki et al., 2009; Yazawa et al., 2007). Recently, two reports described a single mutant allele of TMEM38B as a cause of recessive OI. The authors described an identical mutation that occurs in all affected individuals in three consanguineous families of Saudi Arabian origin (Shaheen et al., 2012) and in three Israeli Bedouin consanguineous families (Volodarsky et al., 2013). In both reports the deletion involved exon 4 of TMEM38B. Concerning the clinical phenotype, our patient has a milder OI phenotype than Bedouin and Saudi Arabian patients regarding bone alterations. Indeed, both Bedouin and Saudi Arabian patients showed limb deformities that are not present in our patient. In the Israel Bedouin families the authors reported the presence of blue sclera in 6 patients, bowed limbs in three patients and mild to moderate short stature in some patients. In all previously reported patients fracture frequency varied but improved after puberty. Moreover, we observed a mild conductive hearing loss not previously reported in association with TMEM38B mutations. As previously described our patient shows a non-syndromic form of OI, with fractures presented at birth that improved after biphosphonate treatments, without dental defects or gray-blue sclera. Unfortunately, information on the presence of limb deformity before surgery and biphosphonate treatment, is not available regarding our patient.
The authors declare no conflict of interest. References Kearney, H.M., Kearney, J.B., Conlin, L.K., 2011. Diagnostic implications of excessive homozygosity detected by SNP-based microarrays: consanguinity, uniparental disomy, and recessive single-gene mutations. Clinics in Laboratory Medicine 31, 595–613. Marini, J.C., Blissett, A.R., 2013. New genes in bone development: what's new in osteogenesis imperfecta. Journal of Clinical Endocrinology and Metabolism 98 (8), 3095–3103. http://dx.doi.org/10.1210/jc.2013-1505 (Aug, Epub 2013 Jun 14). Rohrbach, M., Giunta, C., 2012. Recessive osteogenesis imperfecta: clinical, radiological, and molecular findings. American Journal of Medical Genetics. Part C, Seminars in Medical Genetics 160C, 175–189. Shaheen, R., Alazami, A.M., Alshammari, M.J., et al., 2012. Study of autosomal recessive osteogenesis imperfecta in Arabia reveals a novel locus defined by TMEM38B mutation. Journal of Medical Genetics 49 (10), 630–635. Tarailo-Graovac, M., Chen, N., 2009. Using RepeatMasker to Identify Repetitive Elements in Genomic Sequences. Current Protocols in Bioinformatics 25, 4.10.1–4.10.14. Volodarsky, M., Markus, B., Cohen, I., et al., 2013. A deletion mutation in TMEM38B associated with autosomal recessive osteogenesis imperfecta. Human Mutation 34 (4), 582–586 (Apr). Yamazaki, D., Komazaki, S., Nakanishi, H., Mishima, A., Nishi, M., Yazawa, M., Yamazaki, T., Taguchi, R., Takeshima, H., 2009. Essential role of the TRIC-B channel in Ca2+ handling of alveolar epithelial cells and in perinatal lung maturation. Development 136 (14), 2355–2361. Yazawa, M., Ferrante, C., Feng, J., Mio, K., Ogura, T., Zhang, M., Lin, P.H., Pan, Z., Komazaki, S., Kato, K., Nishi, M., Zhao, X., et al., 2007. TRIC channels are essential for Ca21 handling in intracellular stores. Nature 448 (7149), 78–82.
Please cite this article as: Rubinato, E., et al., A novel deletion mutation involving TMEM38B in a patient with autosomal recessive osteogenesis imperfecta, Gene (2014), http://dx.doi.org/10.1016/j.gene.2014.05.028
Contents lists available at ScienceDirect
Gene journal homepage: www.elsevier.com/locate/gene
A novel deletion mutation involving TMEM38B in a patient with autosomal recessive osteogenesis imperfecta Elisa Rubinato a,⁎, Anna Morgan b, Angela D'Eustacchio b, Vanna Pecile b, Giulia Gortani b, Paolo Gasparini a,b, Flavio Faletra b a b
University of Trieste, Trieste, Italy Institute for Maternal and Child Health, IRCCS “Burlo Garofolo”, Trieste, Italy
a r t i c l e
i n f o
Article history: Received 12 January 2014 Received in revised form 4 May 2014 Accepted 9 May 2014 Available online xxxx Keywords: TMEM38B OI AR SNP array Homozygous deletion
a b s t r a c t Osteogenesis imperfecta (OI) is a hereditary bone disease characterized by decreased bone density and multiple fractures, usually inherited in an autosomal dominant manner. Several gene encoding proteins related to collagen metabolism have been described in some cases of autosomal recessive OI (including CRTAP, LEPRE1, PPIB, FKBP65, SERPINF1, BMP1, WNT1, FKBP10). Recently, TMEM38B, a gene that encodes TRIC-B, a monovalent cation-specific channel involved in calcium flux from intracellular stores and in cell differentiation, has been associated with autosomal recessive OI. Here, we describe the second deletion-mutation involving the TMEM38B gene in an 11 year-old Albanian female with a clinical phenotype of OI, born to parents with suspected consanguinity. SNP array analysis revealed a homozygous region larger than 2 Mb that overlapped with the TMEM38B locus and was characterized by a 35 kb homozygous deletion involving exons 1 and 2 of TMEM38B gene. © 2014 Elsevier B.V. All rights reserved.
1. Introduction Osteogenesis imperfecta (OI) is a hereditary disease characterized by low bone mass with altered bone microarchitecture, leading to increased bone fragility and deformity (Rohrbach and Giunta, 2012). OI is a clinically and genetically heterogeneous disorder, inherited in about 90% of individuals in an autosomal dominant manner. OI etiology is directly or indirectly related to an abnormal synthesis or structure of type I collagen, the most abundant protein of extracellular bone matrix. Type I collagen is a triple helical molecule synthesized as procollagen from COL1A1 and COL1A2, and mutations in these genes are found in the majority of affected individuals (Rohrbach and Giunta, 2012; Marini and Blissett, 2013). However, in the last few years several genes (including CRTAP, LEPRE1, PPIB, FKBP65, SERPINF1, BMP1, WNT1, FKBP10) have been linked to autosomal recessive (AR) forms of OI. Additional, but yet unclassified genes (Marini and Blissett, 2013), including SP7 and TMEM38B, had been associated with AR OI. In particular, a study of multiplex consanguineous families and simplex cases of Saudi Arabian origin revealed that TMEM38B contributes to AR OI in that population (Shaheen et al., 2012). In three families a complete loss of TMEM38B exon 4 (NM_018112.1:c.455_542del) was detected.
Abbreviations: OI, osteogenesis imperfecta; AR, autosomal recessive; PCR, polymerase chain reaction; SNP, single nucleotide polymorphism. ⁎ Corresponding author at: Medical Genetics, Institute for Maternal and Child Health, IRCCS “Burlo Garofolo”, Via dell'Istria 65/1, Trieste, Italy. E-mail address: [email protected] (E. Rubinato).
The same deletion was also described in ten individuals from three independent Israeli Bedouin consanguineous families showing a clinical phenotype compatible with OI type IV (Volodarsky et al., 2013). In all cases a 4.8 Mb region of homozygosity was detected, between marker rs1819743 and marker rs4979370. Within this region the same deletion was demonstrated, suggesting a possible common founder effect. Here we describe a novel AR mutation involving TMEM38B gene, causing a clinical phenotype compatible with OI. 2. Patient and methods 2.1. Clinical report The proband is an 11-year old Albanian girl, born to healthy parents from the same small village, with suspected consanguinity. The parents did not present any limb/spine deformities. She presented with bone fragility, osteopenia and mild conductive hearing loss. The patient had seven fractures at birth, involving both the upper and lower extremities (in particular both femurs, right tibia, right ulna and three ribs). Subsequently in the first seven years of life, eight additional fractures occurred along with generalized demineralization. In particular, femural and tibia fractures required surgical reduction with placements of rods. Given the frequency of fractures and the low mineral density detected (Zscore: − 2.6 sd) the patient underwent several cyclic treatments with bisphosphonate (Neridronate, 2 mg/kg every 90 days). She had a good response in terms of fracture reduction, with no more episodes observed after two years of follow-up, and with increased bone mineral
http://dx.doi.org/10.1016/j.gene.2014.05.028 0378-1119/© 2014 Elsevier B.V. All rights reserved.
Please cite this article as: Rubinato, E., et al., A novel deletion mutation involving TMEM38B in a patient with autosomal recessive osteogenesis imperfecta, Gene (2014), http://dx.doi.org/10.1016/j.gene.2014.05.028
2
E. Rubinato et al. / Gene xxx (2014) xxx–xxx
density (Zscore: − 1.5 sd). Clinically the patient did not have joint hypomobility and she can ambulate independently, without walking aids. Radiographs of lower limbs, lateral spine and skull at 10 years of age, after surgery and bisphosphonate treatment, showed mild demineralization and no bone deformity (Fig. 1). Bilateral mild conductive hearing loss was detected at 10 years old. On visual inspection, she had normal scleral hue, no dysmorphic features and no dentinogenesis imperfecta. The ultrasound examination detected no organ involvement. Echocardiography showed no alterations. Furthermore, her intellectual function was normal. Her height was 140 cm (50° percentile), her weight was 53 kg (95° percentile), without growth deficiency. 2.2. Molecular analysis Molecular analysis of COL1A1 and COL1A2 genes was negative for the presence of causative mutations. Because of the suspected consanguinity between the parents, a SNP array analysis was performed using the Illumina Infinium SNP genotyping platform (HumanOmniExpress — 12 chips and BeadStation Scanner), in order to detect regions of homozygosity encompassing genes known to be involved in recessive forms of OI. Briefly, 200 ng of DNA at a concentration of 50 ng/μL was processed and the genotyping reaction steps were performed according to the manufacturer's specifications. Data analysis was performed using different software such as GenomeStudio 2011.1 (cnv Partition 3.2.0) and PennCNV. Since we demonstrated the presence of homozygous
areas, we used Nexus Copy Number 7.0 software (Biodiscovery, El Segundo, Calif.) to calculate the possible presence of consanguinity. To confirm the deletion and to define the exact breakpoints, a long PCR amplification between the two SNPs was carried out. PCR was performed with KAPA HiFi HotStart ReadyMix (2×), according to manufacturer's protocol (initial step of 5 min at 95 °C, followed by 30 cycles of 20 s at 95 °C, 15 s at 60 °C, and 11 min at 72 °C; Primer Forward-GAGCTGTC ACAATACCTTGTG, Primer Reverse-CACCAATACTATGAACAGGTGA). Then, using internal primers, a 33,891 kb homozygous deletion was characterized (Fig. 1). PCR was performed with KAPA2G Fast HotStart ReadyMix PCR Kit, according to manufacturer's protocol (initial step of 3 min at 96 °C, followed by 30 cycles of 15 s at 96 °C, 15 s at 60 °C, and 1 s at 72 °C; Primer Forward-CACGACCTGTGCTCACTGCA, Primer Reverse-TTGAAACTGACCCACCAGGG). Moreover we studied all the repeat sequences nearby the deletion using a web-tool (http://www. repeatmasker.org) (Tarailo-Graovac and Chen, 2009). 3. Results SNP array analysis revealed several homozygosity regions and among these, only one was larger than 2 Mb (chr9:107,793,426– 109,935,841). This region overlaps with the TMEM38B locus, and was characterized by a 35 kb homozygous deletion spanning from marker rs1567368 to rs9408800 and involving only exons 1 and 2 of TMEM38B gene. To confirm the deletion and to define the exact
Fig. 1. Molecular and radiological findings. A) The area between the (*) represents the largest homozygosity region that overlaps with the TMEM38B locus. The (+) indicates the 35 kb deletion involving exons 1 and 2 of TMEM38B gene. B) Electropherograms of the wild type allele of mother (m) and father (f) and of the mutated allele of mother (m), father (f) and daughter (d). The black arrows show the breakpoints. C) Key radiographs from the proband at 10 years of age (lateral spine, skull and lower limbs).
Please cite this article as: Rubinato, E., et al., A novel deletion mutation involving TMEM38B in a patient with autosomal recessive osteogenesis imperfecta, Gene (2014), http://dx.doi.org/10.1016/j.gene.2014.05.028
E. Rubinato et al. / Gene xxx (2014) xxx–xxx
3
breakpoints, a long PCR amplification between these two SNPs was carried out. Then, using internal primers, a 33,891 kb (chr9: 108.444.592– 108.478.483) deletion was identified (Fig. 1). The deletion was inherited from both parents. To demonstrate the possible presence of consanguinity we checked the overall amount of homozygosity and we found that the total segment homozygosity was almost 19,66 Mb, resulting in a 6th degree of consanguinity (Kearney et al., 2011). Eventually, studying all the repeat sequences near the deletion, we demonstrated the presence of ALU and SINE sequences upstream and of a LINE sequence downstream of the deletion. In particular, we examined 1 kb upstream and 1 kb downstream of the deletion. The ALU/SINE was detected in the position between chr9:108,444,366 and chr9:108,444,664, whereas the LINE/L1 was identified between chr9:108,478,466 and chr9:108,478,878. In both cases the breakpoints were included in the repeat sequences.
Concerning the molecular alteration, we confirmed a 35 kb homozygous deletion involving exons 1 and 2 of TMEM38B gene within a homozygous region larger than 2 Mb that overlapped the TMEM38B gene. Since the deletion was found within a homozygous area, it is very likely that it was due to a common ancestor carrying the mutation. In order to demonstrate it, we used Nexus Copy Number 7.0 software (Biodiscovery, El Segundo, Calif.), and we identified a 6th degree of consanguinity between the parents. Finally, we postulated that the deletion was promoted by the presence of repeat sequences in the segments before and after the breakpoints. In conclusion, our finding expands current knowledge on the role of TMEM38B deletions in causing autosomal recessive OI. Given this novel mutation report and the amount of repeat sequences within and close to this gene, it is possible that additional novel deletions will be discovered in the near future.
4. Discussion
Conflict of interest
In this case report, we identified the second mutation of TMEM38B causing AR OI. TMEM38B encodes an ubiquitously expressed monovalent cation channel protein, TRIC-B (trimeric intracellular cation channel type B), involved in calcium flux from intracellular stores and in cell differentiation (Yamazaki et al., 2009; Yazawa et al., 2007). Recently, two reports described a single mutant allele of TMEM38B as a cause of recessive OI. The authors described an identical mutation that occurs in all affected individuals in three consanguineous families of Saudi Arabian origin (Shaheen et al., 2012) and in three Israeli Bedouin consanguineous families (Volodarsky et al., 2013). In both reports the deletion involved exon 4 of TMEM38B. Concerning the clinical phenotype, our patient has a milder OI phenotype than Bedouin and Saudi Arabian patients regarding bone alterations. Indeed, both Bedouin and Saudi Arabian patients showed limb deformities that are not present in our patient. In the Israel Bedouin families the authors reported the presence of blue sclera in 6 patients, bowed limbs in three patients and mild to moderate short stature in some patients. In all previously reported patients fracture frequency varied but improved after puberty. Moreover, we observed a mild conductive hearing loss not previously reported in association with TMEM38B mutations. As previously described our patient shows a non-syndromic form of OI, with fractures presented at birth that improved after biphosphonate treatments, without dental defects or gray-blue sclera. Unfortunately, information on the presence of limb deformity before surgery and biphosphonate treatment, is not available regarding our patient.
The authors declare no conflict of interest. References Kearney, H.M., Kearney, J.B., Conlin, L.K., 2011. Diagnostic implications of excessive homozygosity detected by SNP-based microarrays: consanguinity, uniparental disomy, and recessive single-gene mutations. Clinics in Laboratory Medicine 31, 595–613. Marini, J.C., Blissett, A.R., 2013. New genes in bone development: what's new in osteogenesis imperfecta. Journal of Clinical Endocrinology and Metabolism 98 (8), 3095–3103. http://dx.doi.org/10.1210/jc.2013-1505 (Aug, Epub 2013 Jun 14). Rohrbach, M., Giunta, C., 2012. Recessive osteogenesis imperfecta: clinical, radiological, and molecular findings. American Journal of Medical Genetics. Part C, Seminars in Medical Genetics 160C, 175–189. Shaheen, R., Alazami, A.M., Alshammari, M.J., et al., 2012. Study of autosomal recessive osteogenesis imperfecta in Arabia reveals a novel locus defined by TMEM38B mutation. Journal of Medical Genetics 49 (10), 630–635. Tarailo-Graovac, M., Chen, N., 2009. Using RepeatMasker to Identify Repetitive Elements in Genomic Sequences. Current Protocols in Bioinformatics 25, 4.10.1–4.10.14. Volodarsky, M., Markus, B., Cohen, I., et al., 2013. A deletion mutation in TMEM38B associated with autosomal recessive osteogenesis imperfecta. Human Mutation 34 (4), 582–586 (Apr). Yamazaki, D., Komazaki, S., Nakanishi, H., Mishima, A., Nishi, M., Yazawa, M., Yamazaki, T., Taguchi, R., Takeshima, H., 2009. Essential role of the TRIC-B channel in Ca2+ handling of alveolar epithelial cells and in perinatal lung maturation. Development 136 (14), 2355–2361. Yazawa, M., Ferrante, C., Feng, J., Mio, K., Ogura, T., Zhang, M., Lin, P.H., Pan, Z., Komazaki, S., Kato, K., Nishi, M., Zhao, X., et al., 2007. TRIC channels are essential for Ca21 handling in intracellular stores. Nature 448 (7149), 78–82.
Please cite this article as: Rubinato, E., et al., A novel deletion mutation involving TMEM38B in a patient with autosomal recessive osteogenesis imperfecta, Gene (2014), http://dx.doi.org/10.1016/j.gene.2014.05.028
