Truncating mutations in the last exon of NOTCH3 cause lateral meningocele syndrome.
Lateral meningocele syndrome (LMS, OMIM%130720), also known as Lehman syndrome, is a very rare skeletal disorder with facial anomalies, hypotonia and meningocele-related neurologic dysfunction. The characteristic lateral meningoceles represent the severe end of the dural ectasia spectrum and are typically most severe in the lower spine. Facial features of LMS include hypertelorism and telecanthus, high arched eyebrows, ptosis, midfacial hypoplasia, micrognathia, high and narrow palate, low-set ears and a hypotonic appearance. Hyperextensibility, hernias and scoliosis reflect a connective tissue abnormality, and aortic dilation, a high-pitched nasal voice, wormian bones and osteolysis may be present. Lateral meningocele syndrome has phenotypic overlap with Hajdu-Cheney syndrome. We performed exome resequencing in five unrelated individuals with LMS and identified heterozygous truncating NOTCH3 mutations. In an additional unrelated individual Sanger sequencing revealed a deleterious variant in the same exon 33. In total, five novel de novo NOTCH3 mutations were identified in six unrelated patients. One had a 26 bp deletion (c.6461_6486del, p.G2154fsTer78), two carried the same single base pair insertion (c.6692_93insC, p.P2231fsTer11), and three individuals had a nonsense point mutation at c.6247A > T (pK2083*), c.6663C > G (p.Y2221*) or c.6732C > A, (p.Y2244*). All mutations cluster into the last coding exon, resulting in premature termination of the protein and truncation of the negative regulatory proline-glutamate-serine-threonine rich PEST domain. Our results suggest that mutant mRNA products escape nonsense mediated decay. The truncated NOTCH3 may cause gain-of-function through decreased clearance of the active intracellular product, resembling NOTCH2 mutations in the clinically related Hajdu-Cheney syndrome and contrasting the NOTCH3 missense mutations causing CADASIL.
Division of Medical Genetics, A.I. duPont Hospital for Children, Wilmington, Delaware, and Sidney Kimmel Medical School at T. Jefferson University, Philadelphia, Pennsylvania.
Karen W
KW
Gripp
Katherine M
KM
Robbins
Nara L
NL
Sobreira
P Dane
PD
Witmer
Lynne M
LM
Bird
Kristiina
K
Avela
Outi
O
Makitie
Daniela
D
Alves
Jacob S
JS
Hogue
Elaine H
EH
Zackai
Kimberly F
KF
Doheny
Deborah L
DL
Stabley
Katia
K
Sol-Church
D000015:Abnormalities, Multiple / Q000175:diagnosis* / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D059472:Exome; D005091:Exons; D019066:Facies; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008588:Meningocele / Q000175:diagnosis* / Q000235:genetics*; D009154:Mutation; D010641:Phenotype; D000071656:Receptor, Notch3; D051880:Receptors, Notch / Q000235:genetics*; D055815:Young Adult
C499374:NOTCH3 protein, human; D000071656:Receptor, Notch3; D051880:Receptors, Notch
Hajdu-Cheney syndrome; Lehman syndrome; NOTCH3; PEST domain; dural ectasia; lateral meningocele syndrome