TY - JOUR
T1 - Mutations in EXTL3 Cause Neuro-immuno-skeletal Dysplasia Syndrome
AU - Oud, Machteld M.
AU - Tuijnenburg, Paul
AU - Hempel, Maja
AU - van Vlies, Naomi
AU - Ren, Zemin
AU - Ferdinandusse, Sacha
AU - Jansen, Machiel H.
AU - Santer, René
AU - Johannsen, Jessika
AU - Bacchelli, Chiara
AU - Alders, Marielle
AU - Li, Rui
AU - Davies, Rosalind
AU - Dupuis, Lucie
AU - Cale, Catherine M.
AU - Wanders, Ronald J. A.
AU - Pals, Steven T.
AU - Ocaka, Louise
AU - James, Chela
AU - Müller, Ingo
AU - Lehmberg, Kai
AU - Strom, Tim
AU - Engels, Hartmut
AU - Williams, Hywel J.
AU - Beales, Phil
AU - Roepman, Ronald
AU - Dias, Patricia
AU - Brunner, Han G.
AU - Cobben, Jan-Maarten
AU - Hall, Christine
AU - Hartley, Taila
AU - Le Quesne Stabej, Polona
AU - Mendoza-Londono, Roberto
AU - Davies, E. Graham
AU - de Sousa, Sérgio B.
AU - Lessel, Davor
AU - Arts, Heleen H.
AU - Kuijpers, Taco W.
PY - 2017
Y1 - 2017
N2 - EXTL3 regulates the biosynthesis of heparan sulfate (HS), important for both skeletal development and hematopoiesis, through the formation of HS proteoglycans (HSPGs). By whole-exome sequencing, we identified homozygous missense mutations c.1382C>T, c.1537C>T, c.1970A>G, and c.2008T>G in EXTL3 in nine affected individuals from five unrelated families. Notably, we found the identical homozygous missense mutation c.1382C>T (p.Pro461Leu) in four affected individuals from two unrelated families. Affected individuals presented with variable skeletal abnormalities and neurodevelopmental defects. Severe combined immunodeficiency (SCID) with a complete absence of T cells was observed in three families. EXTL3 was most abundant in hematopoietic stem cells and early progenitor T cells, which is in line with a SCID phenotype at the level of early T cell development in the thymus. To provide further support for the hypothesis that mutations in EXTL3 cause a neuro-immuno-skeletal dysplasia syndrome, and to gain insight into the pathogenesis of the disorder, we analyzed the localization of EXTL3 in fibroblasts derived from affected individuals and determined glycosaminoglycan concentrations in these cells as well as in urine and blood. We observed abnormal glycosaminoglycan concentrations and increased concentrations of the non-sulfated chondroitin disaccharide D0a0 and the disaccharide D0a4 in serum and urine of all analyzed affected individuals. In summary, we show that biallelic mutations in EXTL3 disturb glycosaminoglycan synthesis and thus lead to a recognizable syndrome characterized by variable expression of skeletal, neurological, and immunological abnormalities
AB - EXTL3 regulates the biosynthesis of heparan sulfate (HS), important for both skeletal development and hematopoiesis, through the formation of HS proteoglycans (HSPGs). By whole-exome sequencing, we identified homozygous missense mutations c.1382C>T, c.1537C>T, c.1970A>G, and c.2008T>G in EXTL3 in nine affected individuals from five unrelated families. Notably, we found the identical homozygous missense mutation c.1382C>T (p.Pro461Leu) in four affected individuals from two unrelated families. Affected individuals presented with variable skeletal abnormalities and neurodevelopmental defects. Severe combined immunodeficiency (SCID) with a complete absence of T cells was observed in three families. EXTL3 was most abundant in hematopoietic stem cells and early progenitor T cells, which is in line with a SCID phenotype at the level of early T cell development in the thymus. To provide further support for the hypothesis that mutations in EXTL3 cause a neuro-immuno-skeletal dysplasia syndrome, and to gain insight into the pathogenesis of the disorder, we analyzed the localization of EXTL3 in fibroblasts derived from affected individuals and determined glycosaminoglycan concentrations in these cells as well as in urine and blood. We observed abnormal glycosaminoglycan concentrations and increased concentrations of the non-sulfated chondroitin disaccharide D0a0 and the disaccharide D0a4 in serum and urine of all analyzed affected individuals. In summary, we show that biallelic mutations in EXTL3 disturb glycosaminoglycan synthesis and thus lead to a recognizable syndrome characterized by variable expression of skeletal, neurological, and immunological abnormalities
U2 - https://doi.org/10.1016/j.ajhg.2017.01.013
DO - https://doi.org/10.1016/j.ajhg.2017.01.013
M3 - Article
C2 - 28132690
SN - 0002-9297
VL - 100
SP - 281
EP - 296
JO - American journal of human genetics
JF - American journal of human genetics
IS - 2
ER -