title: Mutations in KLHL40 are a frequent cause of severe autosomal-recessive nemaline myopathy.
abstract: Nemaline myopathy (NEM) is a common congenital myopathy. At the very severe end of the NEM clinical spectrum are genetically unresolved cases of autosomal-recessive fetal akinesia sequence. We studied a multinational cohort of 143 severe-NEM-affected families lacking genetic diagnosis. We performed whole-exome sequencing of six families and targeted gene sequencing of additional families. We identified 19 mutations in KLHL40 (kelch-like family member 40) in 28 apparently unrelated NEM kindreds of various ethnicities. Accounting for up to 28% of the tested individuals in the Japanese cohort, KLHL40 mutations were found to be the most common cause of this severe form of NEM. Clinical features of affected individuals were severe and distinctive and included fetal akinesia or hypokinesia and contractures, fractures, respiratory failure, and swallowing difficulties at birth. Molecular modeling suggested that the missense substitutions would destabilize the protein. Protein studies showed that KLHL40 is a striated-muscle-specific protein that is absent in KLHL40-associated NEM skeletal muscle. In zebrafish, klhl40a and klhl40b expression is largely confined to the myotome and skeletal muscle, and knockdown of these isoforms results in disruption of muscle structure and loss of movement. We identified KLHL40 mutations as a frequent cause of severe autosomal-recessive NEM and showed that it plays a key role in muscle development and function. Screening of KLHL40 should be a priority in individuals who are affected by autosomal-recessive NEM and who present with prenatal symptoms and/or contractures and in all Japanese individuals with severe NEM.
authors.affiliation: Western Australian Institute for Medical Research and the Centre for Medical Research, University of Western Australia, Nedlands, Western Australia 6009, Australia.
authors.forename: Gianina
authors.initials: G
authors.lastname: Ravenscroft
authors.forename: Satoko
authors.initials: S
authors.lastname: Miyatake
authors.forename: Vilma-Lotta
authors.initials: VL
authors.lastname: Lehtokari
authors.forename: Emily J
authors.initials: EJ
authors.lastname: Todd
authors.forename: Pauliina
authors.initials: P
authors.lastname: Vornanen
authors.forename: Kyle S
authors.initials: KS
authors.lastname: Yau
authors.forename: Yukiko K
authors.initials: YK
authors.lastname: Hayashi
authors.forename: Noriko
authors.initials: N
authors.lastname: Miyake
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Tsurusaki
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Doi
authors.forename: Hirotomo
authors.initials: H
authors.lastname: Saitsu
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Osaka
authors.forename: Sumimasa
authors.initials: S
authors.lastname: Yamashita
authors.forename: Takashi
authors.initials: T
authors.lastname: Ohya
authors.forename: Yuko
authors.initials: Y
authors.lastname: Sakamoto
authors.forename: Eriko
authors.initials: E
authors.lastname: Koshimizu
authors.forename: Shintaro
authors.initials: S
authors.lastname: Imamura
authors.forename: Michiaki
authors.initials: M
authors.lastname: Yamashita
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Ogata
authors.forename: Masaaki
authors.initials: M
authors.lastname: Shiina
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Bryson-Richardson
authors.forename: Raquel
authors.initials: R
authors.lastname: Vaz
authors.forename: Ozge
authors.initials: O
authors.lastname: Ceyhan
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Brownstein
authors.forename: Lindsay C
authors.initials: LC
authors.lastname: Swanson
authors.forename: Sophie
authors.initials: S
authors.lastname: Monnot
authors.forename: Norma B
authors.initials: NB
authors.lastname: Romero
authors.forename: Helge
authors.initials: H
authors.lastname: Amthor
authors.forename: Nina
authors.initials: N
authors.lastname: Kresoje
authors.forename: Padma
authors.initials: P
authors.lastname: Sivadorai
authors.forename: Cathy
authors.initials: C
authors.lastname: Kiraly-Borri
authors.forename: Goknur
authors.initials: G
authors.lastname: Haliloglu
authors.forename: Beril
authors.initials: B
authors.lastname: Talim
authors.forename: Diclehan
authors.initials: D
authors.lastname: Orhan
authors.forename: Gulsev
authors.initials: G
authors.lastname: Kale
authors.forename: Adrian K
authors.initials: AK
authors.lastname: Charles
authors.forename: Victoria A
authors.initials: VA
authors.lastname: Fabian
authors.forename: Mark R
authors.initials: MR
authors.lastname: Davis
authors.forename: Martin
authors.initials: M
authors.lastname: Lammens
authors.forename: Caroline A
authors.initials: CA
authors.lastname: Sewry
authors.forename: Adnan
authors.initials: A
authors.lastname: Manzur
authors.forename: Francesco
authors.initials: F
authors.lastname: Muntoni
authors.forename: Nigel F
authors.initials: NF
authors.lastname: Clarke
authors.forename: Kathryn N
authors.initials: KN
authors.lastname: North
authors.forename: Enrico
authors.initials: E
authors.lastname: Bertini
authors.forename: Yoram
authors.initials: Y
authors.lastname: Nevo
authors.forename: Ekkhard
authors.initials: E
authors.lastname: Willichowski
authors.forename: Inger E
authors.initials: IE
authors.lastname: Silberg
authors.forename: Haluk
authors.initials: H
authors.lastname: Topaloglu
authors.forename: Alan H
authors.initials: AH
authors.lastname: Beggs
authors.forename: Richard J N
authors.initials: RJ
authors.lastname: Allcock
authors.forename: Ichizo
authors.initials: I
authors.lastname: Nishino
authors.forename: Carina
authors.initials: C
authors.lastname: Wallgren-Pettersson
authors.forename: Naomichi
authors.initials: N
authors.lastname: Matsumoto
authors.forename: Nigel G
authors.initials: NG
authors.lastname: Laing
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D044466:Asian People / Q000235:genetics; D015331:Cohort Studies; D016368:Frameshift Mutation; D005808:Genes, Recessive; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000473:pathology*; D020125:Mutation, Missense; D017696:Myopathies, Nemaline / Q000208:ethnology / Q000235:genetics* / Q000473:pathology; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D012720:Severity of Illness Index; D015027:Zebrafish / Q000235:genetics
chemical_list: D009124:Muscle Proteins