title: Identification of KLHL41 Mutations Implicates BTB-Kelch-Mediated Ubiquitination as an Alternate Pathway to Myofibrillar Disruption in Nemaline Myopathy.
abstract: Nemaline myopathy (NM) is a rare congenital muscle disorder primarily affecting skeletal muscles that results in neonatal death in severe cases as a result of associated respiratory insufficiency. NM is thought to be a disease of sarcomeric thin filaments as six of eight known genes whose mutation can cause NM encode components of that structure, however, recent discoveries of mutations in non-thin filament genes has called this model in question. We performed whole-exome sequencing and have identified recessive small deletions and missense changes in the Kelch-like family member 41 gene (KLHL41) in four individuals from unrelated NM families. Sanger sequencing of 116 unrelated individuals with NM identified compound heterozygous changes in KLHL41 in a fifth family. Mutations in KLHL41 showed a clear phenotype-genotype correlation: Frameshift mutations resulted in severe phenotypes with neonatal death, whereas missense changes resulted in impaired motor function with survival into late childhood and/or early adulthood. Functional studies in zebrafish showed that loss of Klhl41 results in highly diminished motor function and myofibrillar disorganization, with nemaline body formation, the pathological hallmark of NM. These studies expand the genetic heterogeneity of NM and implicate a critical role of BTB-Kelch family members in maintenance of sarcomeric integrity in NM.
authors.affiliation: Division of Genetics and Genomics, The Manton Center for Orphan Disease Research, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Vandana A
authors.initials: VA
authors.lastname: Gupta
authors.forename: Gianina
authors.initials: G
authors.lastname: Ravenscroft
authors.forename: Ranad
authors.initials: R
authors.lastname: Shaheen
authors.forename: Emily J
authors.initials: EJ
authors.lastname: Todd
authors.forename: Lindsay C
authors.initials: LC
authors.lastname: Swanson
authors.forename: Masaaki
authors.initials: M
authors.lastname: Shiina
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Ogata
authors.forename: Cynthia
authors.initials: C
authors.lastname: Hsu
authors.forename: Nigel F
authors.initials: NF
authors.lastname: Clarke
authors.forename: Basil T
authors.initials: BT
authors.lastname: Darras
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Farrar
authors.forename: Amal
authors.initials: A
authors.lastname: Hashem
authors.forename: Nicholas D
authors.initials: ND
authors.lastname: Manton
authors.forename: Francesco
authors.initials: F
authors.lastname: Muntoni
authors.forename: Kathryn N
authors.initials: KN
authors.lastname: North
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Sandaradura
authors.forename: Ichizo
authors.initials: I
authors.lastname: Nishino
authors.forename: Yukiko K
authors.initials: YK
authors.lastname: Hayashi
authors.forename: Caroline A
authors.initials: CA
authors.lastname: Sewry
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Thompson
authors.forename: Kyle S
authors.initials: KS
authors.lastname: Yau
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Brownstein
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Yu
authors.forename: Richard J N
authors.initials: RJ
authors.lastname: Allcock
authors.forename: Mark R
authors.initials: MR
authors.lastname: Davis
authors.forename: Carina
authors.initials: C
authors.lastname: Wallgren-Pettersson
authors.forename: Naomichi
authors.initials: N
authors.lastname: Matsumoto
authors.forename: Fowzan S
authors.initials: FS
authors.lastname: Alkuraya
authors.forename: Nigel G
authors.initials: NG
authors.lastname: Laing
authors.forename: Alan H
authors.initials: AH
authors.lastname: Beggs
mesh_terms: D000293:Adolescent; D000818:Animals; D002648:Child; D002675:Child, Preschool; D003598:Cytoskeletal Proteins; D017809:Fatal Outcome; D005260:Female; D015870:Gene Expression; D023061:Gene Order; D056726:Genetic Association Studies; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D008958:Models, Molecular; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D009154:Mutation; D009210:Myofibrils / Q000378:metabolism*; D017696:Myopathies, Nemaline / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism*; D011487:Protein Conformation; D054730:Protein Interaction Domains and Motifs; D011506:Proteins / Q000737:chemistry / Q000235:genetics*; D015398:Signal Transduction; D054875:Ubiquitination; D015027:Zebrafish
chemical_list: D003598:Cytoskeletal Proteins; C586302:KLHL41 protein, human; D011506:Proteins